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1.  Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people 
Lancet  2014;383(9932):1899-1911.
Summary
Background
The associations of blood pressure with the different manifestations of incident cardiovascular disease in a contemporary population have not been compared. In this study, we aimed to analyse the associations of blood pressure with 12 different presentations of cardiovascular disease.
Methods
We used linked electronic health records from 1997 to 2010 in the CALIBER (CArdiovascular research using LInked Bespoke studies and Electronic health Records) programme to assemble a cohort of 1·25 million patients, 30 years of age or older and initially free from cardiovascular disease, a fifth of whom received blood pressure-lowering treatments. We studied the heterogeneity in the age-specific associations of clinically measured blood pressure with 12 acute and chronic cardiovascular diseases, and estimated the lifetime risks (up to 95 years of age) and cardiovascular disease-free life-years lost adjusted for other risk factors at index ages 30, 60, and 80 years. This study is registered at ClinicalTrials.gov, number NCT01164371.
Findings
During 5·2 years median follow-up, we recorded 83 098 initial cardiovascular disease presentations. In each age group, the lowest risk for cardiovascular disease was in people with systolic blood pressure of 90–114 mm Hg and diastolic blood pressure of 60–74 mm Hg, with no evidence of a J-shaped increased risk at lower blood pressures. The effect of high blood pressure varied by cardiovascular disease endpoint, from strongly positive to no effect. Associations with high systolic blood pressure were strongest for intracerebral haemorrhage (hazard ratio 1·44 [95% CI 1·32–1·58]), subarachnoid haemorrhage (1·43 [1·25–1·63]), and stable angina (1·41 [1·36–1·46]), and weakest for abdominal aortic aneurysm (1·08 [1·00–1·17]). Compared with diastolic blood pressure, raised systolic blood pressure had a greater effect on angina, myocardial infarction, and peripheral arterial disease, whereas raised diastolic blood pressure had a greater effect on abdominal aortic aneurysm than did raised systolic pressure. Pulse pressure associations were inverse for abdominal aortic aneurysm (HR per 10 mm Hg 0·91 [95% CI 0·86–0·98]) and strongest for peripheral arterial disease (1·23 [1·20–1·27]). People with hypertension (blood pressure ≥140/90 mm Hg or those receiving blood pressure-lowering drugs) had a lifetime risk of overall cardiovascular disease at 30 years of age of 63·3% (95% CI 62·9–63·8) compared with 46·1% (45·5–46·8) for those with normal blood pressure, and developed cardiovascular disease 5·0 years earlier (95% CI 4·8–5·2). Stable and unstable angina accounted for most (43%) of the cardiovascular disease-free years of life lost associated with hypertension from index age 30 years, whereas heart failure and stable angina accounted for the largest proportion (19% each) of years of life lost from index age 80 years.
Interpretation
The widely held assumptions that blood pressure has strong associations with the occurrence of all cardiovascular diseases across a wide age range, and that diastolic and systolic associations are concordant, are not supported by the findings of this high-resolution study. Despite modern treatments, the lifetime burden of hypertension is substantial. These findings emphasise the need for new blood pressure-lowering strategies, and will help to inform the design of randomised trials to assess them.
Funding
Medical Research Council, National Institute for Health Research, and Wellcome Trust.
doi:10.1016/S0140-6736(14)60685-1
PMCID: PMC4042017  PMID: 24881994
2.  Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial 
European Heart Journal  2012;33(7):857-865.
Aims
High-density lipoprotein cholesterol (HDL-C) is inversely associated with cardiovascular (CV) events and thus an attractive therapeutic target. However, in spite of marked elevations in HDL-C, the first cholesterol transport protein (CETP) inhibitor torcetrapib raised blood pressure (BP), impaired endothelial function, and increased CV mortality and morbidity. Dalcetrapib is a novel molecule acting on CETP with a different chemical structure to torcetrapib. As HDL stimulates nitric oxide (NO), suppresses inflammation, and exerts protective CV effects, we investigated the effects of dalcetrapib on endothelial function, blood pressure, inflammatory markers, and lipids in patients with, or at risk of, coronary heart disease (CHD) in a double-blind randomized placebo-controlled trial (clinicaltrials.gov number NCT00655538).
Methods and results
Patients with target low-density lipoprotein cholesterol (LDL-C) levels received dalcetrapib 600 mg/day or placebo for 36 weeks on top of standard therapy (including statins). The primary outcome measures were the change from baseline of flow-mediated dilatation (%FMD) of the right brachial artery after 5 min of cuff occlusion at 12 weeks and the 24 h ambulatory blood pressure monitoring (ABPM) at week 4. Secondary outcomes included change from baseline in FMD after 36 weeks and the change in ABPM at 12 and 36 weeks, changes in HDL-C, LDL-C, triglycerides, CETP activity, as well as standard safety parameters. Four hundred seventy-six patients were randomized. Baseline FMD was 4.1 ± 2.2 and 4.0 ± 2.4% with placebo or dalcetrapib, respectively and did not change significantly from placebo after 12 and 36 weeks (P = 0.1764 and 0.9515, respectively). After 4, 24, and 36 weeks of treatment with dalcetrapib, CETP activity decreased by 51, 53, and 56% (placebo corrected, all P < 0.0001), while at weeks 4, 12, and 36 HDL-C increased by 25, 27, and 31% (placebo corrected, all P < 0.0001). Low-density lipoprotein cholesterol levels did not change. At baseline, ABPM was 125 ± 12/74 ± 8mmHg in the placebo and 128 ± 11/75 ± 7mmHg in the dalcetrapib group (P = 0.3372 and 0.1248, respectively, placebo-corrected change from baseline) and did not change for up to 36 weeks. Biomarkers of inflammation, oxidative stress, and coagulation did not change during follow-up except for Lp-PLA2 mass levels which increased by 17% (placebo corrected). Overall 7 patients given dalcetrapib and 8 patients given placebo experienced at least one pre-specified adjudicated event (11 events with dalcetrapib and 12 events with placebo).
Conclusion
The dal-VESSEL trial has established the tolerability and safety of CETP-inhibition with dalcetrapib in patients with or at risk of CHD. Dalcetrapib reduced CETP activity and increased HDL-C levels without affecting NO-dependent endothelial function, blood pressure, or markers of inflammation and oxidative stress. The dal-OUTCOMES trial (NCT00658515) will show whether dalcetrapib improves outcomes in spite of a lack of effect on endothelial function.
doi:10.1093/eurheartj/ehs019
PMCID: PMC3345558  PMID: 22345126
High-density; Lipoprotein; Cholesterol (HDL-C); Torcetrapib; Dalcetrapib
3.  Levels of circulating endothelial cells and colony forming units are influenced by age and dyslipidaemia 
Pediatric research  2012;72(3):299-304.
Background
The balance between endothelial injury and repair in childhood is poorly understood. We examined this relationship in healthy children, in adults and in children with familial hypercholesterolaemia (FH).
Methodology
Circulating endothelial cells (CECs) were measured as a marker of vascular injury, with vascular repair assessed by counting colony forming units (CFUs), also known as endothelial progenitor cells.
Results
CEC number increased with age. Children with FH had elevated CECs compared to healthy children , with similar levels numerically to those found in healthy adults. CFU numbers were higher in healthy children than either healthy adults or children with FH. Endothelium dependent vascular function, measured by flow-mediated dilatation (FMD), was positively associated with CFU number, even following adjustment for confounding risk variables.
Conclusion
Levels of CECs increase and CFUs decrease with age. In childhood, before the onset of clinically detectable cardiovascular dysfunction, children with a major risk factor for atherosclerotic disease have levels of these indices of vascular injury and repair approaching those seen in adults.
doi:10.1038/pr.2012.76
PMCID: PMC3604683  PMID: 22785446
4.  A gene-centric study of common carotid artery remodelling 
Atherosclerosis  2013;226(2):440-446.
Background
Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized.
Methods
Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA).
Results
rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08–0.18 mm, P = 8.2 × 10−8). A proxy SNP (rs4916251, R2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case–control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03–1.17, p = 2.8 × 10−3, I2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling.
Conclusions
Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.
Highlights
► In the IMPROVE study (n > 3000) variants at 1q24.3 were strongly associated with larger carotid diameters. ► The lead variant was associated with Abdominal Aortic Aneurysm (AAA) in meta-analysis of 5 studies (n > 50,000). ► Variants at 1q24.3 appear to be associated with vascular remodelling and risk of AAA.
doi:10.1016/j.atherosclerosis.2012.11.002
PMCID: PMC3573227  PMID: 23246012
Abdominal aortic aneurysm; Genome-wide association studies; Vascular remodelling; Carotid artery
5.  Adipose and Height Growth Through Childhood and Blood Pressure Status in a Large Prospective Cohort Study 
Hypertension  2012;59(5):919-925.
Raised blood pressure (BP) is the world’s leading mortality risk factor. Childhood BP substantially predicts adult levels, and although both prenatal and postnatal growth influence it, their relative importance is debated. In a longitudinal study (Avon Longitudinal Study of Parents and Children) of 12 962 healthy children, we aimed to assess the relative contribution of different growth periods and of standardized measures of height versus weight-for-height (an adiposity marker) to BP at age 10 years. Conditional growth modeling was used in the 3230 boys and 3346 girls with BP measurements. Systolic BP was inversely associated with birth weight and weight-for-height but not length (−0.33, −0.27, and −0.12 mm Hg · SD−1; P=0.003, 0.035, and 0.35, respectively). In infancy, weight, weight-for-height, and height gains were all positively associated with systolic BP (0.90, 0.41, and 0.82 mm Hg · SD−1, respectively; all P<0.001). After infancy, all of the growth modalities were positively associated with systolic BP (weight, 1.91; weight-for-height, 1.56; height, 1.20 mm Hg · SD−1; all P<0.001). Similar but weaker associations were found with diastolic BP. Although BP at 10 years was associated with both prenatal and early postnatal growth, their influence was small compared with that of later growth. Because BP ranking relative to the population is substantially determined in the first decade of life, a focus on strategies to reduce the development of adiposity from infancy onward, rather than an emphasis on the nutrition and weight of mothers and infants, should bring greater reductions in population BP.
doi:10.1161/HYPERTENSIONAHA.111.187716
PMCID: PMC3428923  PMID: 22493074
blood pressure; childhood growth; hypertension; obesity; population
7.  Adiposity Is Associated with Blunted Cardiovascular, Neuroendocrine and Cognitive Responses to Acute Mental Stress 
PLoS ONE  2012;7(6):e39143.
Obesity and mental stress are potent risk factors for cardiovascular disease but their relationship with each other is unclear. Resilience to stress may differ according to adiposity. Early studies that addressed this are difficult to interpret due to conflicting findings and limited methods. Recent advances in assessment of cardiovascular stress responses and of fat distribution allow accurate assessment of associations between adiposity and stress responsiveness. We measured responses to the Montreal Imaging Stress Task in healthy men (N = 43) and women (N = 45) with a wide range of BMIs. Heart rate (HR) and blood pressure (BP) measures were used with novel magnetic resonance measures of stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR) and arterial compliance to assess cardiovascular responses. Salivary cortisol and the number and speed of answers to mathematics problems in the task were used to assess neuroendocrine and cognitive responses, respectively. Visceral and subcutaneous fat was measured using T2*-IDEAL. Greater BMI was associated with generalised blunting of cardiovascular (HR:β = −0.50 bpm.unit−1, P = 0.009; SV:β = −0.33 mL.unit−1, P = 0.01; CO:β = −61 mL.min−1.unit−1, P = 0.002; systolic BP:β = −0.41 mmHg.unit−1, P = 0.01; TPR:β = 0.11 WU.unit−1, P = 0.02), cognitive (correct answers: r = −0.28, P = 0.01; time to answer: r = 0.26, P = 0.02) and endocrine responses (cortisol: r = −0.25, P = 0.04) to stress. These associations were largely determined by visceral adiposity except for those related to cognitive performance, which were determined by both visceral and subcutaneous adiposity. Our findings suggest that adiposity is associated with centrally reduced stress responsiveness. Although this may mitigate some long-term health risks of stress responsiveness, reduced performance under stress may be a more immediate negative consequence.
doi:10.1371/journal.pone.0039143
PMCID: PMC3380036  PMID: 22745709
8.  Adiposity and cardiovascular risk factors in a large contemporary population of pre-pubertal children 
European Heart Journal  2010;31(24):3063-3072.
Aims
To examine the associations of several markers of adiposity and a wide range of cardiovascular risk factors and biomarkers in pre-pubertal children.
Methods and results
Four measures of adiposity,body mass index (BMI), waist circumference, dual-energy X-ray absorptiometry (DXA)-determined fat mass, and leptin concentration, were available in up to 7589 children aged 8.8–11.7 (9.9 mean) years from the Avon Longitudinal Study of Parents and Children (ALSPAC). Thirteen per cent of boys and 18.8% of girls were overweight, and 5.3% of boys and 5% of girls were obese. Body mass index was highly correlated with waist circumference (r = 0.91), DXA fat mass (r = 0.87), and leptin concentration (r = 0.75), and all had similar associations with cardiovascular risk factors. A 1 kg/m2 greater BMI was associated with 1.4mmHg (95% CI 1.25–1.44) higher systolic blood pressure (BP). In 5002 children, a 1 kg/m2 greater BMI was associated with a 0.05 mmol/L (95% CI 0.036–0.055) higher non-high-density lipoprotein (HDL) cholesterol and 0.03 mmol/L (95% CI −0.034 to −0.025) lower HDL cholesterol. There were also graded associations with apolipoproteins A1 and B, interleukin-6, and C-reactive protein. Comparing children who were obese with those who were normal weight, the odds ratio for hypertension was 10.7 (95% CI 7.2–15.9) for boys and 13.5 (95% CI 9.4–19.5) for girls.
Conclusion
In pre-pubertal UK children, overweight/obesity is common and has broadly similar associations with BP, HDL cholesterol, and non-HDL cholesterol to those observed in adults. Future research should evaluate whether effective interventions to maintain healthy weight in childhood could have important benefits for adult cardiovascular risk.
doi:10.1093/eurheartj/ehq355
PMCID: PMC3001590  PMID: 20972265
Adiposity; BMI; Children; Cardiovascular risk; ALSPAC
9.  IQ, Educational Attainment, Memory and Plasma Lipids: Associations with Apolipoprotein E Genotype in 5995 Children 
Biological Psychiatry  2011;70(2):152-158.
Background
Apolipoprotein E (APOE) genotype (ε2/ε3/ε4: rs429358 ε4 allele; rs7412 ε2 allele) is strongly associated with both lipid levels and Alzheimer's disease. Although there is also evidence of milder cognitive impairment in later life in carriers of the APOE ε4 allele, there have been few studies investigating the impact of APOE genotype on cognitive function in children.
Methods
We determined APOE genotype in 5995 children from the Avon Longitudinal Study of Parents and Children and investigated associations between APOE genotype and plasma lipids (at age 9), IQ (at age 8), memory (at ages 8 and 10), and performance in school attainment tests (at ages 7, 11, and 14).
Results
Observed genotype group counts were consistent with Hardy–Weinberg equilibrium (χ2p value = .84). There were strong relationships between APOE genotype and low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides, which follow the same patterns as in adults. There was no strong evidence to suggest that APOE genotype was associated with IQ (all p values ≥ .46), memory function (p ≥ .35), or school attainment test results (p ≥ .28).
Conclusion
Although APOE genotype does have strong associations with lipid levels in childhood, there does not seem to be meaningful effects on cognitive performance, suggesting that any detrimental effects of the ε4 allele on cognitive function are not important until later life.
doi:10.1016/j.biopsych.2010.10.033
PMCID: PMC3130925  PMID: 21215387
APOE; children; cognitive function; IQ; lipids; memory
10.  Determinants of vascular phenotype in a large childhood population: the Avon Longitudinal Study of Parents and Children (ALSPAC) 
European Heart Journal  2010;31(12):1502-1510.
Aims
To assess the feasibility and reproducibility of non-invasive vascular assessment in a childhood population setting and identify the determinants of vascular phenotype in early life.
Methods and results
We studied 7557 children (age 9.8–12.3 years) participating in the Avon Longitudinal Study of Parents and Children (ALSPAC). Six research technicians underwent a 5-month training protocol to enable study of brachial artery endothelial function by flow-mediated dilatation (FMD) and arterial stiffness by carotid to radial pulse wave velocity (PWV) and brachial distensibility [distensibility coefficient (DC)]. Reproducibility studies were performed at the beginning, the middle, and the end of the study. A blinded repeat evaluation of a random selection of 3% of the cohort was also undertaken throughout the study. The effect of anthropometric and environmental factors on each measure was examined. Successful measures were obtained in 88, 95, and 87% of the studied children for FMD, PWV, and DC, respectively. The coefficients of variation between technicians for FMD, PWV, and DC were 10.5, 4.6, and 6.6% at the beginning of the study and reached 7.7, 4.1, and 10% at the end. Baseline vessel diameter and gender were important determinants of all the vascular measures, with a small effect of room and skin temperatures on FMD and PWV. Boys consistently had lower FMD and DC and higher PWV measures (P < 0.01 for all).
Conclusion
Reproducible, high-quality assessments of vascular structure and function in children can be made on a large scale in field studies by suitably trained non-specialist operators. This study provides an invaluable resource for assessing the impact of early influences, genetic, and environmental factors on arterial phenotype.
doi:10.1093/eurheartj/ehq062
PMCID: PMC2912638  PMID: 20421227
ALSPAC; Vascular; Children; Endothelial function; Reproducibility
12.  Potent anti-ischaemic effects of statins in chronic stable angina: incremental benefit beyond lipid lowering? 
European Heart Journal  2010;31(21):2650-2659.
Aims
The DoUble-blind Atorvastatin AmLodipine (DUAAL) trial investigated whether atorvastatin decreases ischaemia by a vascular benefit, independent of low-density lipoprotein cholesterol lowering, in patients with coronary artery disease (CAD), both alone and in combination with the traditional anti-anginal therapy, amlodipine.
Methods and results
Randomized, double-blind, parallel-group, multicountry trial (2 weeks run-in and 24 weeks active therapy) comparing three treatments: amlodipine, atorvastatin, and amlodipine + atorvastatin; in 311 patients (78% male; mean age 62 years) with stable angina (≥2 attacks/week), CAD history, ≥3 transient myocardial ischaemia (TMI) episodes, and/or ≥15 min ischaemia on 48 h ambulatory electrocardiographic (AECG) monitoring. Efficacy variables were change in TMI by AECG, exercise ischaemia, angina diary data, and inflammatory biomarkers at Week 26. There was a comparable, highly significant decrease in TMI with amlodipine and atorvastatin, but no additional benefit for the combination. More than 50% of patients became TMI-free in all three groups and this was accompanied by a comparable, marked reduction in angina and nitroglycerin consumption. High-sensitivity C-reactive protein fell by 40% in patients receiving atorvastatin but there was no change with amlodipine. Adverse events were comparable among groups.
Conclusion
Atorvastatin was as potent an anti-ischaemic agent as amlodipine. Future studies of combination therapies will be instructive.
Clinical trial registration information: National clinical trial number: NCT00159718, protocol number A0531031 listed on http://clinicaltrials.gov/.
doi:10.1093/eurheartj/ehq133
PMCID: PMC2966969  PMID: 20494902
Coronary artery disease; Transient myocardial ischaemia; Statin; Combination therapy
13.  Walking speed and subclinical atherosclerosis in healthy older adults: the Whitehall II study 
Heart  2010;96(5):380-384.
Objective
Extended walking speed is a predictor of incident cardiovascular disease (CVD) in older individuals, but the ability of an objective short-distance walking speed test to stratify the severity of preclinical conditions remains unclear. This study examined whether performance in an 8-ft walking speed test is associated with metabolic risk factors and subclinical atherosclerosis.
Design
Cross-sectional.
Setting
Epidemiological cohort.
Participants
530 adults (aged 63±6 years, 50.3% male) from the Whitehall II cohort study with no known history or objective signs of CVD.
Main outcome
Electron beam computed tomography and ultrasound was used to assess the presence and extent of coronary artery calcification (CAC) and carotid intima-media thickness (IMT), respectively.
Results
High levels of CAC (Agatston score >100) were detected in 24% of the sample; the mean IMT was 0.75 mm (SD 0.15). Participants with no detectable CAC completed the walking course 0.16 s (95% CI 0.04 to 0.28) faster than those with CAC ≥400. Objectively assessed, but not self-reported, faster walking speed was associated with a lower risk of high CAC (odds ratio 0.62, 95% CI 0.40 to 0.96) and lower IMT (β=−0.04, 95% CI −0.01 to −0.07 mm) in comparison with the slowest walkers (bottom third), after adjusting for conventional risk factors. Faster walking speed was also associated with lower adiposity, C-reactive protein and low-density lipoprotein cholesterol.
Conclusions
Short-distance walking speed is associated with metabolic risk and subclinical atherosclerosis in older adults without overt CVD. These data suggest that a non-aerobically challenging walking test reflects the presence of underlying vascular disease.
doi:10.1136/hrt.2009.183350
PMCID: PMC2921267  PMID: 19955091
Ageing; atherosclerosis; computed tomography scanning; epidemiology; exercise testing; gait speed; imaging; physical function; risk stratification
14.  Critical appraisal of CRP measurement for the prediction of coronary heart disease events: new data and systematic review of 31 prospective cohorts 
Background Non-uniform reporting of relevant relationships and metrics hampers critical appraisal of the clinical utility of C-reactive protein (CRP) measurement for prediction of later coronary events.
Methods We evaluated the predictive performance of CRP in the Northwick Park Heart Study (NPHS-II) and the Edinburgh Artery Study (EAS) comparing discrimination by area under the ROC curve (AUC), calibration and reclassification. We set the findings in the context of a systematic review of published studies comparing different available and imputed measures of prediction. Risk estimates per-quantile of CRP were pooled using a random effects model to infer the shape of the CRP-coronary event relationship.
Results NPHS-II and EAS (3441 individuals, 309 coronary events): CRP alone provided modest discrimination for coronary heart disease (AUC 0.61 and 0.62 in NPHS-II and EAS, respectively) and only modest improvement in the discrimination of a Framingham-based risk score (FRS) (increment in AUC 0.04 and –0.01, respectively). Risk models based on FRS alone and FRS + CRP were both well calibrated and the net reclassification improvement (NRI) was 8.5% in NPHS-II and 8.8% in EAS with four risk categories, falling to 4.9% and 3.0% for 10-year coronary disease risk threshold of 15%. Systematic review (31 prospective studies 84 063 individuals, 11 252 coronary events): pooled inferred values for the AUC for CRP alone were 0.59 (0.57, 0.61), 0.59 (0.57, 0.61) and 0.57 (0.54, 0.61) for studies of <5, 5–10 and >10 years follow up, respectively. Evidence from 13 studies (7201 cases) indicated that CRP did not consistently improve performance of the Framingham risk score when assessed by discrimination, with AUC increments in the range 0–0.15. Evidence from six studies (2430 cases) showed that CRP provided statistically significant but quantitatively small improvement in calibration of models based on established risk factors in some but not all studies. The wide overlap of CRP values among people who later suffered events and those who did not appeared to be explained by the consistently log-normal distribution of CRP and a graded continuous increment in coronary risk across the whole range of values without a threshold, such that a large proportion of events occurred among the many individuals with near average levels of CRP.
Conclusions CRP does not perform better than the Framingham risk equation for discrimination. The improvement in risk stratification or reclassification from addition of CRP to models based on established risk factors is small and inconsistent. Guidance on the clinical use of CRP measurement in the prediction of coronary events may require updating in light of this large comparative analysis.
doi:10.1093/ije/dyn217
PMCID: PMC2639366  PMID: 18930961
C-reactive protein; prediction; coronary heart disease; primary prevention; risk stratification
15.  Evaluating the causal relevance of diverse risk markers: horizontal systematic review 
Objectives To develop a new methodology to systematically compare evidence across diverse risk markers for coronary heart disease and to compare this evidence with guideline recommendations.
Design “Horizontal” systematic review incorporating different sources of evidence.
Data sources Electronic search of Medline and hand search of guidelines.
Study selection Two reviewers independently determined eligibility of studies across three sources of evidence (observational studies, genetic association studies, and randomised controlled trials) related to four risk markers: depression, exercise, C reactive protein, and type 2 diabetes.
Data extraction For each risk marker, the largest meta-analyses of observational studies and genetic association studies, and meta-analyses or individual randomised controlled trials were analysed.
Results Meta-analyses of observational studies reported adjusted relative risks of coronary heart disease for depression of 1.9 (95% confidence interval 1.5 to 2.4), for top compared with bottom fourths of exercise 0.7 (0.5 to 1.0), for top compared with bottom thirds of C reactive protein 1.6 (1.5 to 1.7), and for diabetes in women 3.0 (2.4 to 3.7) and in men 2.0 (1.8 to 2.3). Prespecified study limitations were more common for depression and exercise. Meta-analyses of studies that allowed formal Mendelian randomisation were identified for C reactive protein (and did not support a causal effect), and were lacking for exercise, diabetes, and depression. Randomised controlled trials were not available for depression, exercise, or C reactive protein in relation to incidence of coronary heart disease, but trials in patients with diabetes showed some preventive effect of glucose control on risk of coronary heart disease. None of the four randomised controlled trials of treating depression in patients with coronary heart disease reduced the risk of further coronary events. Comparisons of this horizontal evidence review with two guidelines published in 2007 showed inconsistencies, with depression prioritised more in the guidelines than in our review.
Conclusions This horizontal systematic review pinpoints deficiencies and strengths in the evidence for depression, exercise, C reactive protein, and diabetes as unconfounded and unbiased causes of coronary heart disease. This new method could be used to develop a field synopsis and prioritise future development of guidelines and research.
doi:10.1136/bmj.b4265
PMCID: PMC2773829  PMID: 19892791
16.  Genetic Variation in VEGF Does Not Contribute Significantly to the Risk of Congenital Cardiovascular Malformation 
PLoS ONE  2009;4(3):e4978.
Several previous studies have investigated the role of common promoter variants in the vascular endothelial growth factor (VEGF) gene in causing congenital cardiovascular malformation (CVM). However, results have been discrepant between studies and no study to date has comprehensively characterised variation throughout the gene. We genotyped 771 CVM cases, of whom 595 had the outflow tract malformation Tetralogy of Fallot (TOF), and carried out TDT and case-control analyses using haplotype-tagging SNPs in VEGF. We carried out a meta-analysis of previous case-control or family-based studies that had typed VEGF promoter SNPs, which included an additional 570 CVM cases. To identify rare variants potentially causative of CVM, we carried out mutation screening in all VEGF exons and splice sites in 93 TOF cases. There was no significant effect of any VEGF haplotype-tagging SNP on the risk of CVM in our analyses of 771 probands. When the results of this and all previous studies were combined, there was no significant effect of the VEGF promoter SNPs rs699947 (OR 1.05 [95% CI 0.95–1.17]); rs1570360 (OR 1.17 [95% CI 0.99–1.26]); and rs2010963 (OR 1.04 [95% CI 0.93–1.16]) on the risk of CVM in 1341 cases. Mutation screening of 93 TOF cases revealed no VEGF coding sequence variants and no changes at splice consensus sequences. Genetic variation in VEGF appears to play a small role, if any, in outflow tract CVM susceptibility.
doi:10.1371/journal.pone.0004978
PMCID: PMC2654913  PMID: 19308252
17.  International Day for the Evaluation of Abdominal Obesity (IDEA): a study of waist circumference, cardiovascular disease, and diabetes mellitus in 168,000 primary care patients in 63 countries 
Circulation  2007;116(17):1942-1951.
Background
Abdominal adiposity is a growing clinical and public health problem. It is not known whether it is similarly associated with cardiovascular disease (CVD) and diabetes in different regions around the world, and thus whether measuring waist circumference (WC) in addition to body mass index (BMI) is useful in primary care practice.
Methods and Results
Randomly chosen primary care physicians (PCPs) in 63 countries recruited consecutive patients aged 18 to 80 years, on two pre-specified half-days. WC and BMI were measured and the presence of CVD and diabetes recorded. Of the patients consulting the PCPs, 97% agreed to participate in this study. Overall, 24% of 69,409 men and 27% of 98,750 women were obese (BMI ≥ 30 kg/m2). A further 40% and 30% of men and women, respectively, were overweight (BMI 25 to 30 kg/m2). In men and women, respectively, increased WC (>102/88cm, men/women) was recorded in 29% and 48%, CVD in 16% and 13%, and diabetes in 13% and 11%. There was a statistically significant graded increase in the frequency of CVD and diabetes with both BMI and WC, with a stronger relationship for WC than for BMI across regions, for both genders. This relationship between WC, CVD and particularly diabetes was seen even in lean patients (BMI <25 kg/m2).
Conclusions
Among men and women consulting PCPs, BMI and particularly WC were both strongly linked to CVD and especially to diabetes. Strategies to address this global problem are required to prevent an epidemic of these major causes of morbidity and mortality.
doi:10.1161/CIRCULATIONAHA.106.676379
PMCID: PMC2475527  PMID: 17965405
cardiovascular disease; diabetes mellitus; epidemiology; obesity; risk factors; Abdominal Fat; Adiposity; Adolescent; Adult; Aged; 80 and over; Body Mass Index; Cardiovascular Diseases; epidemiology; etiology; Diabetes Mellitus; Female; Humans; International Cooperation; Male; Middle Aged; Obesity; complications; Physicians; Family; Primary Health Care; Random Allocation; World Health
18.  An assessment of composite measures of hospital performance and associated mortality for patients with acute myocardial infarction. Analysis of individual hospital performance and outcome for the National Institute for Cardiovascular Outcomes Research (NICOR) 
Aim:
To investigate whether a hospital-specific opportunity-based composite score (OBCS) was associated with mortality in 136,392 patients with acute myocardial infarction (AMI) using data from the Myocardial Ischaemia National Audit Project (MINAP) 2008–2009.
Methods and results:
For 199 hospitals a multidimensional hospital OBCS was calculated on the number of times that aspirin, thienopyridine, angiotensin-converting enzyme inhibitor (ACEi), statin, β-blocker, and referral for cardiac rehabilitation was given to individual patients, divided by the overall number of opportunities that hospitals had to give that care. OBCS and its six components were compared using funnel plots. Associations between OBCS performance and 30-day and 6-month all-cause mortality were quantified using mixed-effects regression analysis. Median hospital OBCS was 95.3% (range 75.8–100%). By OBCS, 24.1% of hospitals were below funnel plot 99.8% CI, compared to aspirin (11.1%), thienopyridine (15.1%), β-blockers (14.7%), ACEi (19.1%), statins (12.1%), and cardiac rehabilitation (17.6%) on discharge. Mortality (95% CI) decreased with increasing hospital OBCS quartile at 30 days [Q1, 2.25% (2.07–2.43%) vs. Q4, 1.40% (1.25–1.56%)] and 6 months [Q1, 7.93% (7.61–8.25%) vs. Q4, 5.53% (5.22–5.83%)]. Hospital OBCS quartile was inversely associated with adjusted 30-day and 6-month mortality [OR (95% CI), 0.87 (0.80–0.94) and 0.92 (0.88–0.96), respectively] and persisted after adjustment for coronary artery catheterization [0.89 (0.82–0.96) and 0.95 (0.91–0.98), respectively].
Conclusions:
Multidimensional hospital OBCS in AMI survivors are high, discriminate hospital performance more readily than single performance indicators, and significantly inversely predict early and longer-term mortality.
doi:10.1177/2048872612469132
PMCID: PMC3760578  PMID: 24062929
Acute myocardial infarction; composite performance indicators; mortality; performance; quality of care

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