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ABSTRACT: Activation of blood coagulation and fibrinolysis may be associated with increased risk of coronary heart disease. We aimed to assess associations of circulating tissue plasminogen activator (t-PA) antigen, D-dimer and von Willebrand factor (VWF) with coronary heart disease risk.
Prospective case-control study, systematic review and meta-analyses.
Measurements were made in 1925 people who had a first-ever nonfatal myocardial infarction or died of coronary heart disease during follow-up (median 19.4 years) and in 3616 controls nested within the prospective population-based Reykjavik Study.
Age and sex-adjusted odds ratios for coronary heart disease per 1 standard deviation higher baseline level were 1.25 (1.18, 1.33) for t-PA antigen, 1.01 (0.95, 1.07) for D-dimer and 1.11 (1.05, 1.18) for VWF. After additional adjustment for conventional cardiovascular risk factors, corresponding odds ratios were 1.07 (0.99, 1.14) for t-PA antigen, 1.06 (1.00, 1.13) for D-dimer and 1.08 (1.02, 1.15) for VWF. When combined with the results from previous prospective studies in a random-effects meta-analysis, overall adjusted odds ratios were 1.13 (1.06, 1.21) for t-PA antigen (13 studies, 5494 cases), 1.23 (1.16, 1.32) with D-dimer (18 studies, 6799 cases) and 1.16 (1.10, 1.22) with VWF (15 studies, 6556 cases).
Concentrations of t-PA antigen, D-dimer and VWF may be more modestly associated with first-ever CHD events than previously reported. More detailed analysis is required to clarify whether these markers are causal risk factors or simply correlates of coronary heart disease.
PLoS ONE 01/2013; 8(2):e55175. · 4.09 Impact Factor
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Stephen Kaptoge, Emanuele Di Angelantonio,
Lisa Pennells,
Angela M Wood,
Ian R White,
Pei Gao,
Matthew Walker,
Alexander Thompson,
Nadeem Sarwar,
Muriel Caslake, [......],
Gordon D O Lowe,
Nicholas J Wareham,
Kay-Tee Khaw,
Naveed Sattar,
Chris J Packard,
Vilmundur Gudnason,
Paul M Ridker,
Mark B Pepys,
Simon G Thompson,
John Danesh
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ABSTRACT: There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events.
We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen.
The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P<0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (<10%), "intermediate" (10% to <20%), and "high" (≥20%) (P<0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of ≥20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years.
In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.).
New England Journal of Medicine 10/2012; 367(14):1310-20. · 53.30 Impact Factor
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ABSTRACT: AimsTo 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 resultsIn 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.ConclusionN-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 registrationWOSCOPS was carried out and completed prior to the requirement for clinical trial registration.
European Heart Journal 08/2012; · 10.48 Impact Factor
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Circulation Cardiovascular Genetics 08/2012; 5(4):387-90. · 6.11 Impact Factor
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Emanuele Di Angelantonio,
Pei Gao,
Lisa Pennells,
Stephen Kaptoge,
Muriel Caslake,
Alexander Thompson,
Adam S Butterworth,
Nadeem Sarwar,
David Wormser,
Danish Saleheen, [......],
Jukka T Salonen,
William J Howard,
Børge G Nordestgaard,
Angela M Wood,
Simon G Thompson,
S Matthijs Boekholdt,
Naveed Sattar,
Chris Packard,
Vilmundur Gudnason,
John Danesh
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ABSTRACT: The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated.
To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction.
Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years).
Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk.
The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines.
In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.
JAMA The Journal of the American Medical Association 06/2012; 307(23):2499-506. · 30.03 Impact Factor
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Nadeem Sarwar,
Adam S Butterworth,
Daniel F Freitag,
John Gregson,
Peter Willeit,
Donal N Gorman,
Pei Gao,
Danish Saleheen,
Augusto Rendon,
Christopher P Nelson, [......],
Alison H Goodall,
Paul M Ridker,
Hilma Hólm,
Hugh Watkins,
Willem H Ouwehand,
Nilesh J Samani,
Stephen Kaptoge, Emanuele Di Angelantonio,
Olivier Harari,
John Danesh
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ABSTRACT: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.
In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125,222 participants. We also compared the frequency of Asp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6.
The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes.
Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.
British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.
The Lancet 03/2012; 379(9822):1205-13. · 38.28 Impact Factor
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ABSTRACT: We aimed to compare the predictive capabilities of N-terminal pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) for risk of cardiovascular disease (CVD) in older men with and without pre-existing CVD.
The clinical utility of NT-proBNP in CVD risk stratification in the general population remains unclear.
A prospective study of 3,649 men age 60 to 79 years were followed for a mean of 9 years during which there were 608 major CVD events (major fatal and nonfatal coronary heart disease, stroke, and CVD death).
NT-proBNP was significantly associated with risk of all major CVD outcomes after adjustment for CV risk factors in both men with and without CVD. The adjusted standardized hazard ratios for CVD events in those without pre-existing CVD and those with pre-existing CVD were 1.49 (95% confidence interval [CI]: 1.33 to 1.65) and 1.52 (95% CI: 1.33 to 1.75), respectively. CRP was associated with CVD outcomes only in men without pre-existing CVD (adjusted standardized hazard ratios: 1.22 [95% CI: 1.10 to 1.34] and 1.00 [95% CI: 0.86 to 1.38], respectively). NT-proBNP was more strongly associated with CVD outcome than CRP, particularly among those with pre-existing CVD. Inclusion of NT-proBNP in a Framingham-based model yielded significant improvement in C-statistics in both men with and without CVD and resulted in a net reclassification improvement of 8.8% (p = 0.0009) and 8.2% (p < 0.05), respectively, for major CVD events. Inclusion of CRP in the Framingham-based model did not improve prediction in either group (net reclassification improvement 3.8% and 0.6%, respectively).
NT-proBNP, but not CRP, improved prediction of major CVD events in older men with and without pre-existing CVD.
Journal of the American College of Cardiology 06/2011; 58(1):56-64. · 14.16 Impact Factor
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ABSTRACT: Previous studies have shown that plasma levels of haemostatic and inflammatory markers are associated with risk of coronary heart disease (CHD). As haemostatic markers are also acute-phase reactants, it is not clear if their association with CHD is independent of inflammatory markers and established cardiovascular risk factors.
We used a prospective incident case-control study design nested in two cohorts from Sweden. Baseline measurements of a panel of cardiovascular risk factors and eight established markers of haemostasis or inflammation were assessed in 469 first-ever myocardial infarction (MI) cases and 895 matched controls.
After adjustment for baseline values of established risk factors, von Willebrand factor appeared to have the strongest association with MI among the haemostatic markers assayed, with an odds ratio of 2.52 (95% CI, 1.72-3.67) for a comparison of individuals in extreme thirds of baseline levels. For a similar comparison, after adjustment for established risk factors and haemostatic markers, odds ratios for IL-6 and CRP were 1.67 (95% CI, 1.08-2.60) and 1.58 (95% CI, 1.03-2.41), respectively. The relative predictive ability of the individual markers over and above established risk factors was modest according to comparisons of Area under the Receiver Operating Characteristic (AUROC) curves. However, when all eight markers were combined in a single model, the AUROC curve was significantly increased to 0.820 (95% CI, 0.795-0.846) compared to 0.762 (95% CI, 0.732-0.791) for established risk factors only.
These findings suggest that haemostasis and inflammation have at least partially separate roles in risk of myocardial infarction.
Thrombosis Research 06/2011; 129(1):68-73. · 2.44 Impact Factor
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David Wormser,
Stephen Kaptoge, Emanuele Di Angelantonio,
Angela M Wood,
Lisa Pennells,
Alex Thompson,
Nadeem Sarwar,
Jorge R Kizer,
Debbie A Lawlor,
Børge G Nordestgaard,
Paul Ridker,
Veikko Salomaa,
June Stevens,
Mark Woodward,
Naveed Sattar,
Rory Collins,
Simon G Thompson,
Gary Whitlock,
John Danesh
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ABSTRACT: Guidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction when information is available for other risk factors. We studied the separate and combined associations of body-mass index (BMI), waist circumference, and waist-to-hip ratio with risk of first-onset cardiovascular disease.
We used individual records from 58 cohorts to calculate hazard ratios (HRs) per 1 SD higher baseline values (4.56 kg/m(2) higher BMI, 12.6 cm higher waist circumference, and 0.083 higher waist-to-hip ratio) and measures of risk discrimination and reclassification. Serial adiposity assessments were used to calculate regression dilution ratios.
Individual records were available for 221,934 people in 17 countries (14,297 incident cardiovascular disease outcomes; 1.87 million person-years at risk). Serial adiposity assessments were made in up to 63,821 people (mean interval 5.7 years [SD 3.9]). In people with BMI of 20 kg/m(2) or higher, HRs for cardiovascular disease were 1.23 (95% CI 1.17-1.29) with BMI, 1.27 (1.20-1.33) with waist circumference, and 1.25 (1.19-1.31) with waist-to-hip ratio, after adjustment for age, sex, and smoking status. After further adjustment for baseline systolic blood pressure, history of diabetes, and total and HDL cholesterol, corresponding HRs were 1.07 (1.03-1.11) with BMI, 1.10 (1.05-1.14) with waist circumference, and 1.12 (1.08-1.15) with waist-to-hip ratio. Addition of information on BMI, waist circumference, or waist-to-hip ratio to a cardiovascular disease risk prediction model containing conventional risk factors did not importantly improve risk discrimination (C-index changes of -0.0001, -0.0001, and 0.0008, respectively), nor classification of participants to categories of predicted 10-year risk (net reclassification improvement -0.19%, -0.05%, and -0.05%, respectively). Findings were similar when adiposity measures were considered in combination. Reproducibility was greater for BMI (regression dilution ratio 0.95, 95% CI 0.93-0.97) than for waist circumference (0.86, 0.83-0.89) or waist-to-hip ratio (0.63, 0.57-0.70).
BMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids.
British Heart Foundation and UK Medical Research Council.
The Lancet 03/2011; 377(9771):1085-95. · 38.28 Impact Factor
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Sreenivasa Rao Kondapally Seshasai,
Stephen Kaptoge,
Alexander Thompson, Emanuele Di Angelantonio,
Pei Gao,
Nadeem Sarwar,
Peter H Whincup,
Kenneth J Mukamal,
Richard F Gillum,
Ingar Holme, [......],
Astrid Fletcher,
Peter Nilsson,
Sarah Lewington,
Rory Collins,
Vilmundur Gudnason,
Simon G Thompson,
Naveed Sattar,
Elizabeth Selvin,
Frank B Hu,
John Danesh
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ABSTRACT: The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain.
We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies.
After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths.
In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).
New England Journal of Medicine 03/2011; 364(9):829-41. · 53.30 Impact Factor
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ABSTRACT: To determine whether C-reactive protein (CRP) in combination with a stroke risk stratification scheme can help in identifying transesophageal echocardiographic (TEE) markers of thromboembolism such as left atrial (LA)/left atrial appendage (LAA) thrombus, severe LA/LAA spontaneous echocardiographic contrast (SEC), and aortic plaque ≥ 4 mm.
Transthoracic echocardiography, TEE, and CRP measurement were performed at admission in 178 patients with non-valvular atrial fibrillation not receiving oral anticoagulant therapy. Patients were classified as at low, moderate, or high risk of thromboembolism based on seven clinical risk stratification schemes (SPAF, CHADS(2), Framingham, Birmingham/NICE, ACC/AHA/ESC 2006 guidelines, ACCP 2008, CHA(2)DS(2)VASc).
Severe LA/LAA SEC, LA/LAA thrombus, and aortic plaque ≥ 4 mm were present in 6.2%, 6.7%, and 10.1% of patients, respectively. The combination of CRP with a cut-off value of 3.4 mg/L with the Birmingham/Nice or ACC/AHA/ESC 2006 risk score, led to a negative predictive value of 100% in low-risk patients and 91% in moderate-risk patients. For the detection of severe LA/LAA SEC or thrombus, a good discrimination (area under curve ≥ 0.70) using only clinical risk markers was observed for all classifications except for the Framingham and CHADS(2) risk scores. The addition of CRP did not improve the detection of LA/LAA SEC or thrombus, or of severe LA/LAA SEC, thrombus, or aortic plaque.
The combination of clinical risk markers and CRP can help to exclude the presence of the TEE markers LA/LAA SEC or LA/LAA thrombus, particularly in patients classified at low or moderate risk of stroke.
International journal of cardiology 03/2011; 159(1):40-6. · 7.08 Impact Factor
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Frances Wensley,
Pei Gao,
Stephen Burgess,
Stephen Kaptoge, Emanuele Di Angelantonio,
Tina Shah,
James C Engert,
Robert Clarke,
George Davey-Smith,
Børge G Nordestgaard, [......],
Nilesh J Samani,
Manjinder Sandhu,
Sonia Anand,
Mark B Pepys,
Liam Smeeth,
John Whittaker,
Juan Pablo Casas,
Simon G Thompson,
Aroon D Hingorani,
John Danesh
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ABSTRACT: To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease.
Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries.
194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors.
Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals.
CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P<10(-34)) and were unrelated to other risk factors. Risk ratios for coronary heart disease per additional copy of an allele associated with raised C reactive protein were 0.93 (95% confidence interval 0.87 to 1.00) for rs3093077; 1.00 (0.98 to 1.02) for rs1205; 0.98 (0.96 to 1.00) for rs1130864; and 0.99 (0.94 to 1.03) for rs1800947. In a combined analysis, the risk ratio for coronary heart disease was 1.00 (0.90 to 1.13) per 1 SD higher genetically raised natural log (ln) concentration of C reactive protein. The genetic findings were discordant with the risk ratio observed for coronary heart disease of 1.33 (1.23 to 1.43) per 1 SD higher circulating ln concentration of C reactive protein in prospective studies (P=0.001 for difference).
Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease.
BMJ (Clinical research ed.). 01/2011; 342:d548.
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ABSTRACT: To evaluate the association of chocolate consumption with the risk of developing cardiometabolic disorders.
Systematic review and meta-analysis of randomised controlled trials and observational studies.
Medline, Embase, Cochrane Library, PubMed, CINAHL, IPA, Web of Science, Scopus, Pascal, reference lists of relevant studies to October 2010, and email contact with authors.
Randomised trials and cohort, case-control, and cross sectional studies carried out in human adults, in which the association between chocolate consumption and the risk of outcomes related to cardiometabolic disorders were reported.
Data were extracted by two independent investigators, and a consensus was reached with the involvement of a third. The primary outcome was cardiometabolic disorders, including cardiovascular disease (coronary heart disease and stroke), diabetes, and metabolic syndrome. A meta-analysis assessed the risk of developing cardiometabolic disorders by comparing the highest and lowest level of chocolate consumption.
From 4576 references seven studies met the inclusion criteria (including 114,009 participants). None of the studies was a randomised trial, six were cohort studies, and one a cross sectional study. Large variation was observed between these seven studies for measurement of chocolate consumption, methods, and outcomes evaluated. Five of the seven studies reported a beneficial association between higher levels of chocolate consumption and the risk of cardiometabolic disorders. The highest levels of chocolate consumption were associated with a 37% reduction in cardiovascular disease (relative risk 0.63 (95% confidence interval 0.44 to 0.90)) and a 29% reduction in stroke compared with the lowest levels.
Based on observational evidence, levels of chocolate consumption seem to be associated with a substantial reduction in the risk of cardiometabolic disorders. Further experimental studies are required to confirm a potentially beneficial effect of chocolate consumption.
BMJ (Clinical research ed.). 01/2011; 343:d4488.
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Laurence Bal,
Stéphane Ederhy, Emanuele Di Angelantonio,
Florence Toti,
Fatiha Zobairi,
Ghislaine Dufaitre,
Catherine Meuleman,
Ziad Mallat,
Franck Boccara,
Alain Tedgui,
Jean Marie Freyssinet,
Ariel Cohen
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ABSTRACT: We investigated whether circulating procoagulant microparticles (CPMPs) contributed to hypercoagulability in 45 patients with acute pulmonary embolism (APE) and in 45 controls with and 45 controls without cardiovascular risk factors. Concentrations of CPMPs and platelet-derived microparticles (PMPs) were statistically significantly higher in patients with APE than in controls without cardiovascular risk factors. PMPs appeared to be the main source of procoagulant microparticle release in APE, but this correlation disappeared when APE patients were compared to controls with cardiovascular risk factors. CPMPs may have a role in venous thrombosis as mediators of cardiovascular risk factors.
International journal of cardiology 11/2010; 145(2):321-2. · 7.08 Impact Factor
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Stefano De Castro,
Federica Papetti, Emanuele Di Angelantonio,
Biljana Razmovska,
Giovanni Truscelli,
Ursula Tuderti,
Emanuele Puca,
Agata Correnti,
Marco Fiorelli,
Massimiliano Prencipe,
Danilo Toni
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ABSTRACT: We evaluated the feasibility and clinical utility of transesophageal echocardiography (TEE) in the early management of ischemic stroke. TEE was performed in consecutive patients with acute cerebral ischemia within 48 hours of symptoms onset. The data were analyzed by age (<55 vs ≥55 years), and the baseline stroke etiology was classified (determined vs undetermined). TEE was feasible in 660 (61%) of 1,080 patients. Left atrial abnormalities and complicated aortic plaques prevailed in older patients (p <0.05), irrespective of the stroke etiology. A patent foramen ovale prevailed in younger patients (p <0.05) but even in older patients was present in 13% of the determined and 31% of the undetermined stroke subgroups. Overall, high-risk and potentially high-risk cardioembolic sources were detected in 47% of the patients, and stroke etiology was consequently reviewed: 40% of the baseline undetermined strokes were reclassified as cardioembolic, and 29% of lacunar, 42% of large artery, and 30% of other determined-cause strokes were reclassified as concurrent etiology. Subsequently, according to the current guidelines, 12% of patients were reassigned from antiplatelet to anticoagulant therapy and 17% of patients were treated with high-dose statins; overall, secondary prevention treatment was modified in 26% of patients. In conclusion, TEE was feasible in about 2/3 of the patients investigated within 48 hours of the index event, contributed to stroke classification in 1/3 of cases, and guided secondary prevention therapy in 1/4 of patients. Therefore, TEE is useful for defining patients' risk profile for stroke recurrence.
The American journal of cardiology 11/2010; 106(9):1339-44. · 3.58 Impact Factor
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Danish Saleheen,
Nicole Soranzo,
Asif Rasheed,
Hubert Scharnagl,
Rhian Gwilliam,
Myriam Alexander,
Michael Inouye,
Moazzam Zaidi,
Simon Potter,
Philip Haycock, [......],
Ralph McGinnis,
Frank Dudbridge,
Bernhard R Winkelmann,
Bernhard Böehm,
Simon Thompson,
Willem Ouwehand,
Winfried März,
Philippe Frossard,
John Danesh,
Panos Deloukas
[show abstract]
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ABSTRACT: Evidence is sparse about the genetic determinants of major lipids in Pakistanis.
Variants (n=45 000) across 2000 genes were assessed in 3200 Pakistanis and compared with 2450 Germans using the same gene array and similar lipid assays. We also did a meta-analysis of selected lipid-related variants in Europeans. Pakistani genetic architecture was distinct from that of several ethnic groups represented in international reference samples. Forty-one variants at 14 loci were significantly associated with levels of HDL-C, triglyceride, or LDL-C. The most significant lipid-related variants identified among Pakistanis corresponded to genes previously shown to be relevant to Europeans, such as CETP associated with HDL-C levels (rs711752; P<10(-13)), APOA5/ZNF259 (rs651821; P<10(-13)) and GCKR (rs1260326; P<10(-13)) with triglyceride levels; and CELSR2 variants with LDL-C levels (rs646776; P<10(-9)). For Pakistanis, these 41 variants explained 6.2%, 7.1%, and 0.9% of the variation in HDL-C, triglyceride, and LDL-C, respectively. Compared with Europeans, the allele frequency of rs662799 in APOA5 among Pakistanis was higher and its impact on triglyceride concentration was greater (P-value for difference <10(-4)).
Several lipid-related genetic variants are common to Pakistanis and Europeans, though they explain only a modest proportion of population variation in lipid concentration. Allelic frequencies and effect sizes of lipid-related variants can differ between Pakistanis and Europeans.
Circulation Cardiovascular Genetics 08/2010; 3(4):348-57. · 6.11 Impact Factor
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Danish Saleheen,
Myriam Alexander,
Asif Rasheed,
David Wormser,
Nicole Soranzo,
Naomi Hammond,
Adam Butterworth,
Moazzam Zaidi,
Philip Haycock,
Suzannah Bumpstead, [......],
Faisal Shahid,
Zehra Memon,
Shahzad Majeed Bhatti,
Waleed Kayani,
Syed Saadat Ali,
Muhammad Fahim,
Muhammad Ishaq,
Philippe Frossard,
Panos Deloukas,
John Danesh
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ABSTRACT: To examine variants at the 9p21 locus in a case-control study of acute myocardial infarction (MI) in Pakistanis and to perform an updated meta-analysis of published studies in people of European ancestry.
A total of 1851 patients with first-ever confirmed MI and 1903 controls were genotyped for 89 tagging single-nucleotide polymorphisms at locus 9p21, including the lead variant (rs1333049) identified by the Wellcome Trust Case Control Consortium. Minor allele frequencies and extent of linkage disequilibrium observed in Pakistanis were broadly similar to those seen in Europeans. In the Pakistani study, 6 variants were associated with MI (P<10(-2)) in the initial sample set, and in an additional 741 cases and 674 controls in whom further genotyping was performed for these variants. For Pakistanis, the odds ratio for MI was 1.13 (95% CI, 1.05 to 1.22; P=2 x 10(-3)) for each copy of the C allele at rs1333049. In comparison, a meta-analysis of studies in Europeans yielded an odds ratio of 1.31 (95% CI, 1.26 to 1.37) for the same variant (P=1 x 10(-3) for heterogeneity). Meta-analyses of 23 variants, in up to 38,250 cases and 84,820 controls generally yielded higher values in Europeans than in Pakistanis.
To our knowledge, this study provides the first demonstration that variants at the 9p21 locus are significantly associated with MI risk in Pakistanis. However, association signals at this locus were weaker in Pakistanis than those in European studies.
Arteriosclerosis Thrombosis and Vascular Biology 07/2010; 30(7):1467-73. · 6.37 Impact Factor
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ABSTRACT: The purpose of this study was to assess the association of apolipoprotein(a) (apo[a]) isoforms with cardiovascular disease risk.
Although circulating lipoprotein(a) (Lp[a]) is likely to be a causal risk factor in coronary heart disease (CHD), the magnitude of this association is modest. Lipoprotein(a) particles with smaller, rather than larger, apo(a) isoforms may be stronger risk factors.
Information was collated from 40 studies published between January 1970 and June 2009 that reported on associations between apo(a) isoforms and risk of CHD or ischemic stroke (involving a total of 11,396 patients and 46,938 controls).
Thirty-six studies used broadly comparable phenotyping and analytic methods to assess apo(a) isoform size. These studies yielded a combined relative risk for CHD of 2.08 (95% confidence intervals [CI]: 1.67 to 2.58) for individuals with smaller versus larger apo(a) isoforms (corresponding approximately to 22 or fewer kringle IV type 2 repeats vs. >22 repeats or analogously an apo[a] molecular weight of <640 kDa vs. > or =640 kDa). There was substantial heterogeneity among these studies (I(2) = 85%, 80% to 89%), which was mainly explained by differences in the laboratory methods and analytic approaches used. In the 6 studies of ischemic stroke that used comparable phenotypic methods, the combined relative risk was 2.14 (1.85 to 2.97). Overall, however, only 3 studies made allowances for Lp(a) concentration.
People with smaller apo(a) isoforms have an approximately 2-fold higher risk of CHD or ischemic stroke than those with larger proteins. Further studies are needed to determine whether the impact of smaller apo(a) isoforms is independent from Lp(a) concentration and other risk factors.
Journal of the American College of Cardiology 05/2010; 55(19):2160-7. · 14.16 Impact Factor
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Alexander Thompson,
Pei Gao,
Lia Orfei,
Sarah Watson, Emanuele Di Angelantonio,
Stephen Kaptoge,
Christie Ballantyne,
Christopher P Cannon,
Michael Criqui,
Mary Cushman,
Albert Hofman,
Chris Packard,
Simon G Thompson,
Rory Collins,
John Danesh
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ABSTRACT: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA(2) mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances.
With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA(2) or other risk factor. The primary outcome was coronary heart disease.
Lp-PLA(2) activity and mass were associated with each other (r=0.51, 95% CI 0.47-0.56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA(2) activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1.10 (95% CI 1.05-1.16) with Lp-PLA(2) activity and 1.11 (1.07-1.16) with Lp-PLA(2) mass for coronary heart disease; 1.08 (0.97-1.20) and 1.14 (1.02-1.27) for ischaemic stroke; 1.16 (1.09-1.24) and 1.13 (1.05-1.22) for vascular mortality; and 1.10 (1.04-1.17) and 1.10 (1.03-1.18) for non-vascular mortality, respectively. RRs with Lp-PLA(2) did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA(2) mass. Adjusted RRs for coronary heart disease were 1.10 (1.02-1.18) with non-HDL cholesterol and 1.10 (1.00-1.21) with systolic blood pressure.
Lp-PLA(2) activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA(2) mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids.
UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.
The Lancet 05/2010; 375(9725):1536-44. · 38.28 Impact Factor
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Nadeem Sarwar,
Manjinder S Sandhu,
Sally L Ricketts,
Adam S Butterworth, Emanuele Di Angelantonio,
S Matthijs Boekholdt,
Willem Ouwehand,
Hugh Watkins,
Nilesh J Samani,
Danish Saleheen,
Debbie Lawlor,
Muredach P Reilly,
Aroon D Hingorani,
Philippa J Talmud,
John Danesh
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ABSTRACT: Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality.
We assessed the -1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20,842 patients with coronary heart disease, 35,206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12,785 incident cases of coronary heart disease during 2.79 million person-years at risk). We analysed -1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy.
The minor allele frequency of -1131T>C was 8% (95% CI 7-9). -1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3.5% [95% CI 2.6-4.6]; 0.053 mmol/L [0.039-0.068]), lower apolipoprotein AI (1.3% [0.3-2.3]; 0.023 g/L [0.005-0.041]), and higher apolipoprotein B (3.2% [1.3-5.1]; 0.027 g/L [0.011-0.043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16.0% (95% CI 12.9-18.7), or 0.25 mmol/L (0.20-0.29), higher (p=4.4x10(-24)). The odds ratio for coronary heart disease was 1.18 (95% CI 1.11-1.26; p=2.6x10(-7)) per C allele, which was concordant with the hazard ratio of 1.10 (95% CI 1.08-1.12) per 16% higher triglyceride concentration recorded in prospective studies. -1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12.2 nmol/L [95% CI 7.7-16.7]; p=9.3x10(-8)) and smaller HDL particle size (0.14 nm [0.08-0.20]; p=7.0x10(-5)), factors that could mediate the effects of triglyceride.
These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease.
British Heart Foundation, UK Medical Research Council, Novartis.
The Lancet 05/2010; 375(9726):1634-9. · 38.28 Impact Factor
