Background

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.

Methods

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.

Results

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.

Conclusions

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.

Purpose

DNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease (CVD). The hypothesis is that DNA damage accumulating with age may induce cell death, which promotes formation of unstable plaques. Defects in DNA repair mechanisms may therefore increase the risk of CVD events. We examined whether the joints effect of common genetic variants in 5 DNA repair pathways may influence the risk of CVD events.

Methods

The PLINK set-based test was used to examine the association to myocardial infarction (MI) of the DNA repair pathway in GWAS data of 866 subjects of the GENetic DEterminants of Restenosis (GENDER) study and 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. We included the main DNA repair pathways (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end-joining (NHEJ)) in the analysis.

Results

The NHEJ pathway was associated with the occurrence of MI in both GENDER (P = 0.0083) and PROSPER (P = 0.014). This association was mainly driven by genetic variation in the MRE11A gene (PGENDER = 0.0001 and PPROSPER = 0.002). The homologous recombination pathway was associated with MI in GENDER only (P = 0.011), for the other pathways no associations were observed.

Conclusion

This is the first study analyzing the joint effect of common genetic variation in DNA repair pathways and the risk of CVD events, demonstrating an association between the NHEJ pathway and MI in 2 different cohorts.

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

Author Summary

Levels of thyroid hormones are tightly regulated by TSH produced in the pituitary, and even mild alterations in their concentrations are strong indicators of thyroid pathologies, which are very common worldwide. To identify common genetic variants associated with the highly heritable markers of thyroid function, TSH and FT4, we conducted a meta-analysis of genome-wide association studies in 26,420 and 17,520 individuals, respectively, of European ancestry with normal thyroid function. Our analysis identified 26 independent genetic variants regulating these traits, several of which are new, and confirmed previously detected polymorphisms affecting TSH (within the PDE8B gene and near CAPZB, MAF/LOC440389, and NR3C2) and FT4 (within DIO1) levels. Gender-specific differences in the genetic effects of several variants for TSH and FT4 levels were identified at several loci, which offer clues to understand the known sexual dimorphism in thyroid function and pathology. Of particular clinical interest, we show that TSH-associated loci contribute not only to normal variation, but also to TSH values outside reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings add to the developing landscape of the regulation of thyroid homeostasis and the consequences of genetic variation for thyroid related diseases.

Introduction

Cyclooxygenase 2 (COX-2) inhibitors have less upper gastrointestinal toxicity than traditional non-steroidal anti-inflammatory drugs (NSAIDs). However, both COX-2 inhibitors and traditional NSAIDs may be associated with adverse cardiovascular side effects. Data from randomised and observational studies suggest that celecoxib has similar cardiovascular toxicity to traditional NSAIDs. The overall safety balance of a strategy of celecoxib therapy versus traditional NSAID therapy is unknown. The European Medicines Agency  requested studies of the cardiovascular safety of celecoxib within Europe. The Standard care versus Celecoxib Outcome Trial (SCOT) compares the cardiovascular safety of celecoxib with traditional NSAID therapy in the setting of the European Union healthcare system.

Methods and analysis

SCOT is a large streamlined safety study conducted in Scotland, England, Denmark and the Netherlands using the Prospective Randomised Open Blinded Endpoint design. Patients aged over 60 years with osteoarthritis or rheumatoid arthritis, free from established cardiovascular disease and requiring chronic NSAID therapy, are randomised to celecoxib or their previous traditional NSAID. They are then followed up for events by record-linkage within their normal healthcare setting. The hypothesis is non-inferiority with a confidence limit of 1.4. The primary endpoint is the first occurrence of hospitalisation or death for the Anti-Platelet Trialists’ Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are (1) first hospitalisation or death for upper gastrointestinal ulcer complications (bleeding, perforation or obstruction); (2) first occurrence of hospitalised upper gastrointestinal ulcer complications or APTC endpoint; (3) first hospitalisation for heart failure; (4) first hospitalisation for APTC endpoint plus heart failure; (5) all-cause mortality and (6) first hospitalisation for new or worsening renal failure.

Ethics and dissemination

SCOT has been approved by the relevant ethics committees. The trial results will be published in a peer-reviewed scientific journal.

Clinical trials registration number

Clinicaltrials.gov (NCT00447759).

Variability in blood pressure predicts cardiovascular disease in young- and middle-aged subjects, but relevant data for older individuals are sparse. We analysed data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study of 5804 participants aged 70–82 years with a history of, or risk factors for cardiovascular disease. Visit-to-visit variability in blood pressure (standard deviation) was determined using a minimum of five measurements over 1 year; an inception cohort of 4819 subjects had subsequent in-trial 3 years follow-up; longer-term follow-up (mean 7.1 years) was available for 1808 subjects. Higher systolic blood pressure variability independently predicted long-term follow-up vascular and total mortality (hazard ratio per 5 mmHg increase in standard deviation of systolic blood pressure = 1.2, 95% confidence interval 1.1–1.4; hazard ratio 1.1, 95% confidence interval 1.1–1.2, respectively). Variability in diastolic blood pressure associated with increased risk for coronary events (hazard ratio 1.5, 95% confidence interval 1.2–1.8 for each 5 mmHg increase), heart failure hospitalisation (hazard ratio 1.4, 95% confidence interval 1.1–1.8) and vascular (hazard ratio 1.4, 95% confidence interval 1.1–1.7) and total mortality (hazard ratio 1.3, 95% confidence interval 1.1–1.5), all in long-term follow-up. Pulse pressure variability was associated with increased stroke risk (hazard ratio 1.2, 95% confidence interval 1.0–1.4 for each 5 mmHg increase), vascular mortality (hazard ratio 1.2, 95% confidence interval 1.0–1.3) and total mortality (hazard ratio 1.1, 95% confidence interval 1.0–1.2), all in long-term follow-up. All associations were independent of respective mean blood pressure levels, age, gender, in-trial treatment group (pravastatin or placebo) and prior vascular disease and cardiovascular disease risk factors. Our observations suggest variability in diastolic blood pressure is more strongly associated with vascular or total mortality than is systolic pressure variability in older high-risk subjects.

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.

Aims

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.

Conclusion

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.

Aims

We explored the effect of treatment with ivabradine, a pure heart rate-slowing agent, on recurrent hospitalizations for worsening heart failure (HF) in the SHIFT trial.

Methods and results

SHIFT was a double-blind clinical trial in which 6505 patients with moderate-to-severe HF and left ventricular systolic dysfunction, all of whom had been hospitalized for HF during the preceding year, were randomized to ivabradine or to placebo on a background of guideline-recommended HF therapy (including maximized β-blockade). In total, 1186 patients experienced at least one additional HF hospitalization during the study, 472 suffered at least two, and 218 suffered at least 3. Patients with additional HF hospitalizations had more severe disease than those without. Ivabradine was associated with fewer total HF hospitalizations [902 vs. 1211 events with placebo; incidence rate ratio, 0.75, 95% confidence interval (CI), 0.65–0.87, P = 0.0002] during the 22.9-month median follow-up. Ivabradine-treated patients evidenced lower risk for a second or third additional HF hospitalization [hazard ratio (HR): 0.66, 95% CI, 0.55–0.79, P < 0.001 and HR: 0.71, 95% CI, 0.54–0.93, P = 0.012, respectively]. Similar observations were made for all-cause and cardiovascular hospitalizations.

Conclusion

Treatment with ivabradine, on a background of guidelines-based HF therapy, is associated with a substantial reduction in the likelihood of recurrent hospitalizations for worsening HF. This benefit can be expected to improve the quality of life and to substantially reduce health-care costs.

Aims

Men and women differ in terms of presentation and management in coronary artery disease (CAD). Whether these differences translate into different clinical outcomes in stable CAD is unclear. We analysed data from the international prospective CLARIFY registry to compare cardiovascular clinical outcomes in men and women with stable CAD.

Methods and results

We analysed 1-year outcomes in 30 977 outpatients with stable CAD [23 975 (77.4%) men; 7002 (22.6%) women]. Women were older than men, more likely to have hypertension and diabetes, and less likely to exercise or smoke. They had more frequent angina, but were less likely to have undergone diagnostic non-invasive testing or coronary angiography. Women received less optimized treatment for stable CAD. One-year outcomes were similar for men and women for the composite of cardiovascular death, non-fatal myocardial infarction, or stroke [adjusted rates 1.7 vs. 1.8%, respectively, odds ratio (OR) 0.93, 95% confidence interval (CI) 0.75–1.15]; all-cause death (adjusted 1.5 vs. 1.6%, OR: 0.91, 95% CI: 0.72–1.13); fatal or non-fatal myocardial infarction (adjusted 1.0 vs. 0.9%, OR: 0.81, 95 CI: 0.60–1.08); and cardiovascular death or non-fatal myocardial infarction (adjusted 1.4 vs. 1.4%, OR: 0.89, 95% CI: 0.70–1.12). Fewer women underwent revascularization (2.6 vs. 2.2%, OR: 0.77, 95% CI: 0.64–0.93), although appropriateness was not analysed.

Conclusion

The risk profiles of women and men with stable CAD differ substantially. However, 1-year outcomes were similar. Fewer women underwent revascularization. Further research is needed to better understand gender determinants of outcome and devise strategies to minimize bias in the management and treatment of women.

Background

The pathophysiology of myocardial injury and repair in patients with ST‐elevation myocardial infarction is incompletely understood. We investigated the relationships among culprit artery microvascular resistance, myocardial salvage, and ventricular function.

Methods and Results

The index of microvascular resistance (IMR) was measured by means of a pressure‐ and temperature‐sensitive coronary guidewire in 108 patients with ST‐elevation myocardial infarction (83% male) at the end of primary percutaneous coronary intervention. Paired cardiac MRI (cardiac magnetic resonance) scans were performed early (2 days; n=108) and late (3 months; n=96) after myocardial infarction. T2‐weighted‐ and late gadolinium–enhanced cardiac magnetic resonance delineated the ischemic area at risk and infarct size, respectively. Myocardial salvage was calculated by subtracting infarct size from area at risk. Univariable and multivariable models were constructed to determine the impact of IMR on cardiac magnetic resonance–derived surrogate outcomes. The median (interquartile range) IMR was 28 (17–42) mm Hg/s. The median (interquartile range) area at risk was 32% (24%–41%) of left ventricular mass, and the myocardial salvage index was 21% (11%–43%). IMR was a significant multivariable predictor of early myocardial salvage, with a multiplicative effect of 0.87 (95% confidence interval 0.82 to 0.92) per 20% increase in IMR; P<0.001. In patients with anterior myocardial infarction, IMR was a multivariable predictor of early and late myocardial salvage, with multiplicative effects of 0.82 (95% confidence interval 0.75 to 0.90; P<0.001) and 0.92 (95% confidence interval 0.88 to 0.96; P<0.001), respectively. IMR also predicted the presence and extent of microvascular obstruction and myocardial hemorrhage.

Conclusion

Microvascular resistance measured during primary percutaneous coronary intervention significantly predicts myocardial salvage, infarct characteristics, and left ventricular ejection fraction in patients with ST‐elevation myocardial infarction. (J Am Heart Assoc. 2012;1:e002246 doi: 10.1161/JAHA.112.002246)

Statin therapy reduces the risk of coronary heart disease (CHD), however, the person-to-person variability in response to statin therapy is not well understood. We have investigated the effect of genetic variation on the reduction of CHD events by pravastatin. First, we conducted a genome-wide association study of 682 CHD cases from the Cholesterol and Recurrent Events (CARE) trial and 383 CHD cases from the West of Scotland Coronary Prevention Study (WOSCOPS), two randomized, placebo-controlled studies of pravastatin. In a combined case-only analysis, 79 single nucleotide polymorphisms (SNPs) were associated with differential CHD event reduction by pravastatin according to genotype (P<0.0001), and these SNPs were analyzed in a second stage that included cases as well as non-cases from CARE and WOSCOPS and patients from the PROspective Study of Pravastatin in the Elderly at Risk/PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease (PROSPER/PHASE), a randomized placebo controlled study of pravastatin in the elderly. We found that one of these SNPs (rs13279522) was associated with differential CHD event reduction by pravastatin therapy in all 3 studies: P = 0.002 in CARE, P = 0.01 in WOSCOPS, P = 0.002 in PROSPER/PHASE. In a combined analysis of CARE, WOSCOPS, and PROSPER/PHASE, the hazard ratio for CHD when comparing pravastatin with placebo decreased by a factor of 0.63 (95% CI: 0.52 to 0.75) for each extra copy of the minor allele (P = 4.8×10−7). This SNP is located in DnaJ homolog subfamily C member 5B (DNAJC5B) and merits investigation in additional randomized studies of pravastatin and other statins.

Background

Heart rate (HR) is an emerging risk factor in coronary artery disease (CAD). However, there is little contemporary data regarding HR and the use of HR-lowering medications, particularly beta-blockers, among patients with stable CAD in routine clinical practice. The goal of the present analysis was to describe HR in such patients, overall and in relation to beta-blocker use, and to describe the determinants of HR.

Methods and Findings

CLARIFY is an international, prospective, observational, longitudinal registry of outpatients with stable CAD, defined as prior myocardial infarction or revascularization procedure, evidence of coronary stenosis of >50%, or chest pain associated with proven myocardial ischemia. A total of 33,438 patients from 45 countries in Europe, the Americas, Africa, Middle East, and Asia/Pacific were enrolled between November 2009 and July 2010. Most of the 33,177 patients included in this analysis were men (77.5%). Mean (SD) age was 64.2 (10.5) years, HR by pulse was 68.3 (10.6) bpm, and by electrocardiogram was 67.2 (11.4) bpm. Overall, 44.0% had HR≥70 bpm. Beta-blockers were used in 75.1% of patients and another 14.4% had intolerance or contraindications to beta-blocker therapy. Among 24,910 patients on beta-blockers, 41.1% had HR≥70 bpm. HR≥70 bpm was independently associated with higher prevalence and severity of angina, more frequent evidence of myocardial ischemia, and lack of use of HR-lowering agents.

Conclusions

Despite a high rate of use of beta-blockers, stable CAD patients often have resting HR≥70 bpm, which was associated with an overall worse health status, more frequent angina and ischemia. Further HR lowering is possible in many patients with CAD. Whether it will improve symptoms and outcomes is being tested.

Trial Registration

Controlled-Trials.com ISRCTN43070564

Summary

Background

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.

Methods

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.

Findings

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.

Interpretation

The human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation.

Funding

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.

Background

Fibrin fragment D-dimer is one of several peptides produced when cross-linked fibrin is degraded by plasmin, and is the most widely-used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.

Methods and Results

A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21,052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ~2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (p-value 6.4×10−52) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (p-value 2.4×10−14) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (p-value 2.9×10−18) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099, 0.096, and 0.061 unit difference, respectively, in natural-log transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for non-synonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.

Conclusions

Three genes were associated with fibrin D-dimer levels, of which the F3 association was the strongest and has not been previously reported.

Background

The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly.

Methods

The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification.

Results

Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results.

Conclusion

With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.

Background

Plasma concentrations of C-reactive protein (CRP), a marker of chronic inflammation, have been associated with cognitive impairment in old age. However, it is unknown whether CRP is causally linked to cognitive decline.

Methods and Findings

Within the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial, with 5680 participants with a mean age of 75 years, we examined associations of CRP levels and its genetic determinants with cognitive performance and decline over 3.2 years mean follow-up. Higher plasma CRP concentrations were associated with poorer baseline performance on the Stroop test (P = 0.001) and Letter Digit Tests (P<0.001), but not with the immediate and delayed Picture Learning Test (PLT; both P>0.5). In the prospective analyses, higher CRP concentrations associated with increased rate of decline in the immediate PLT (P = 0.016), but not in other cognitive tests (all p>0.11). Adjustment for prevalent cardiovascular risk factors and disease did not change the baseline associations nor associations with cognitive decline during follow-up. Four haplotypes of CRP were used and, compared to the common haplotype, carrierships associated strongly with levels of CRP (all P<0.007). In comparison to strong associations of apolipoprotein E with cognitive measures, associations of CRP haplotypes with such measures were inconsistent.

Conclusion

Plasma CRP concentrations associate with cognitive performance in part through pathways independent of (risk factors for) cardiovascular disease. However, lifelong exposure to higher CRP levels does not associate with poorer cognitive performance in old age. The current data weaken the argument for a causal role of CRP in cognitive performance, but further study is warranted to draw definitive conclusions.

Aims

The SHIFT echocardiographic substudy evaluated the effects of ivabradine on left ventricular (LV) remodelling in heart failure (HF).

Methods and results

Eligible patients had chronic HF and systolic dysfunction [LV ejection fraction (LVEF) ≤35%], were in sinus rhythm, and had resting heart rate ≥70 bpm. Patients were randomly allocated to ivabradine or placebo, superimposed on background therapy for HF. Complete echocardiographic data at baseline and 8 months were available for 411 patients (ivabradine 208, placebo 203). Treatment with ivabradine reduced LVESVI (primary substudy endpoint) vs. placebo [−7.0 ± 16.3 vs. −0.9 ± 17.1 mL/m2; difference (SE), −5.8 (1.6), 95% CI −8.8 to −2.7, P< 0.001]. The reduction in LVESVI was independent of beta-blocker use, HF aetiology, and baseline LVEF. Ivabradine also improved LV end-diastolic volume index (−7.9 ± 18.9 vs. −1.8 ± 19.0 mL/m2, P= 0.002) and LVEF (+2.4 ± 7.7 vs. −0.1 ± 8.0%, P< 0.001). The incidence of the SHIFT primary composite outcome (cardiovascular mortality or hospitalization for worsening HF) was higher in patients with LVESVI above the median (59 mL/m2) at baseline (HR 1.62, 95% CI 1.03–2.56, P= 0.04). Patients with the largest relative reductions in LVESVI had the lowest event rates.

Conclusion

Ivabradine reverses cardiac remodelling in patients with HF and LV systolic dysfunction.

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Background

Venous thromboembolic events (VTE), including deep venous thrombosis and pulmonary embolism, are common in older age. It has been suggested that statins might reduce the risk of VTE however positive results from studies of middle aged subjects may not be generalisable to elderly people. We aimed to determine the effect of pravastatin on incident VTE in older people; we also studied the impact of clinical and plasma risk variables.

Methods

This study was an analysis of incident VTE using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), a randomized, double-blind, placebo-controlled trial of pravastatin in men and women aged 70-82. Mean follow-up was 3.2 years. Risk for VTE was examined in non-warfarin treated pravastatin (n = 2834) and placebo (n = 2865) patients using a Cox's proportional hazard model, and the impact of other risk factors assessed in a multivariate forward stepwise regression analysis. Baseline clinical characteristics, blood biochemistry and hematology variables, plasma levels of lipids and lipoproteins, and plasma markers of inflammation and adiposity were compared. Plasma markers of thrombosis and hemostasis were assessed in a nested case (n = 48) control (n = 93) study where the cohort was those participants, not on warfarin, for whom data were available.

Results

There were 28 definite cases (1.0%) of incident VTE in the pravastatin group recipients and 20 cases (0.70%) in placebo recipients. Pravastatin did not reduce VTE in PROSPER compared to placebo [unadjusted hazard ratio (95% confidence interval) 1.42 (0.80, 2.52) p = 0.23]. Higher body mass index (BMI) [1.09 (1.02, 1.15) p = 0.0075], country [Scotland vs Netherlands 4.26 (1.00, 18.21) p = 0.050 and Ireland vs Netherlands 6.16 (1.46, 26.00) p = 0.013], lower systolic blood pressure [1.35 (1.03, 1.75) p = 0.027] and lower baseline Mini Mental State Examination (MMSE) score [1.19 (1.01, 1.41) p = 0.034] were associated with an increased risk of VTE, however only BMI, country and systolic blood pressure remained significant on multivariate analysis. In a nested case control study of definite VTE, plasma Factor VIII levels were associated with VTE [1.52 (1.01, 2.28), p = 0.044]. However no other measure of thrombosis and haemostasis was associated with increased risk of VTE.

Conclusions

Pravastatin does not prevent VTE in elderly people at risk of vascular disease. Blood markers of haemostasis and inflammation are not strongly predictive of VTE in older age however BMI, country and lower systolic blood pressure are independently associated with VTE risk.

Trial Registration

Not applicable when study undertaken.

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Patients with diabetes mellitus and symptomatic coronary artery disease are also likely to be hypertensive and, overall, are at very high cardiovascular (CV) risk. This paper reports the findings of a posthoc analysis of the 1113 patients with diabetes mellitus in the ACTION trial: ACTION itself showed that outcomes in patients with stable angina and hypertension were significantly improved when a long-acting calcium channel blocking drug (nifedipine GITS) was added to their treatment regimens. This further analysis of the ACTION database in those patients with diabetes has identified a number of practical therapeutic issues which are still relevant because of potential outcome benefits, particularly in relation to BP control. For example, despite background CV treatment and, specifically, despite the widespread use of ACE Inhibitor drugs, the addition of nifedipine GITS was associated with significant benefits: improvement in BP control by an average of 6/3 mmHg and significant improvements in outcome. In summary, this retrospective analysis has identified that the addition of nifedipine GITS resulted in improved BP control and significant outcome benefits in patients with diabetes who were at high CV risk. There is evidence to suggest that these findings are of direct relevance to current therapeutic practice.

A single nucleotide polymorphism (SNP) in KIF6, a member of the KIF9 family of kinesins, is associated with differential coronary event reduction from statin therapy in four randomized controlled trials; this SNP (rs20455) is also associated with the risk for coronary heart disease (CHD) in multiple prospective studies. We investigated whether other common SNPs in the KIF6 region were associated with event reduction from statin therapy. Of the 170 SNPs in the KIF6 region investigated in the Cholesterol and Recurrent Events trial (CARE), 28 were associated with differential event reduction from statin therapy (Pinteraction < 0.1 in Caucasians, adjusted for age and sex) and were further investigated in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI22) and West of Scotland Coronary Prevention Study (WOSCOPS). These analyses revealed that two SNPs (rs9462535 and rs9471077), in addition to rs20455, were associated with event reduction from statin therapy (Pinteraction < 0.1 in each of the three studies). The relative risk reduction ranged from 37 to 50% (P < 0.01) in carriers of the minor alleles of these SNPs and from −4 to 13% (P > 0.4) in non-carriers. These three SNPs are in high linkage disequilibrium with one another (r2 > 0.84). Functional studies of these variants may help to understand the role of KIF6 in the pathogenesis of CHD and differential response to statin therapy.

Electronic supplementary material

The online version of this article (doi:10.1007/s00439-010-0892-6) contains supplementary material, which is available to authorized users.

Background

Melatonin is extensively used in the USA in a non-regulated manner for sleep disorders. Prolonged release melatonin (PRM) is licensed in Europe and other countries for the short term treatment of primary insomnia in patients aged 55 years and over. However, a clear definition of the target patient population and well-controlled studies of long-term efficacy and safety are lacking. It is known that melatonin production declines with age. Some young insomnia patients also may have low melatonin levels. The study investigated whether older age or low melatonin excretion is a better predictor of response to PRM, whether the efficacy observed in short-term studies is sustained during continued treatment and the long term safety of such treatment.

Methods

Adult outpatients (791, aged 18-80 years) with primary insomnia, were treated with placebo (2 weeks) and then randomized, double-blind to 3 weeks with PRM or placebo nightly. PRM patients continued whereas placebo completers were re-randomized 1:1 to PRM or placebo for 26 weeks with 2 weeks of single-blind placebo run-out. Main outcome measures were sleep latency derived from a sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of Life (World Health Organzaton-5) Clinical Global Impression of Improvement (CGI-I) and adverse effects and vital signs recorded at each visit.

Results

On the primary efficacy variable, sleep latency, the effects of PRM (3 weeks) in patients with low endogenous melatonin (6-sulphatoxymelatonin [6-SMT] ≤8 μg/night) regardless of age did not differ from the placebo, whereas PRM significantly reduced sleep latency compared to the placebo in elderly patients regardless of melatonin levels (-19.1 versus -1.7 min; P = 0.002). The effects on sleep latency and additional sleep and daytime parameters that improved with PRM were maintained or enhanced over the 6-month period with no signs of tolerance. Most adverse events were mild in severity with no clinically relevant differences between PRM and placebo for any safety outcome.

Conclusions

The results demonstrate short- and long-term efficacy and safety of PRM in elderly insomnia patients. Low melatonin production regardless of age is not useful in predicting responses to melatonin therapy in insomnia. The age cut-off for response warrants further investigation.

Purpose

PERFORM is exploring the efficacy of terutroban versus aspirin for secondary prevention in patients with a history of ischemic stroke or transient ischemic attacks (TIAs). The PERFORM Vascular Project will evaluate the effect of terutroban on progression of atherosclerosis, as assessed by change in carotid intima-media thickness (CIMT) in a subgroup of patients.

Methods and results

The Vascular Project includes structural (CIMT, carotid plaques) and functional (carotid stiffness) vascular studies in all patients showing at least one carotid plaque at entry. Expected mean follow-up is 36 months. Primary endpoint is rate of change of CIMT. Secondary endpoints include emergent plaques and assessment of carotid stiffness. 1,100 patients are required for 90% statistical power to detect treatment-related CIMT difference of 0.025 mm. The first patient was randomized in April 2006.

Conclusions

The PERFORM Vascular Project will investigate terutroban’s effect on vascular structure and function in patients with a history of ischemic stroke or TIAs.

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.