Association of Repeatedly Measured High-Sensitivity-Assayed Troponin I with Cardiovascular Disease Events in a General Population from the MORGAM/BiomarCaRE Study.

BACKGROUND: High-sensitivity troponin I (hs-cTnI) concentrations reflect myocardial stress. The role of hs-cTnI in predicting long-term changes in the risk of cardiovascular disease (CVD) in general populations is not clearly defined. METHODS: We investigated whether the change in 3 repeated measures of hs-cTnI collected 5 years apart in a prospective Danish study (3875 participants, initially aged 30-60 years, 51% female, disease free at baseline) improves 10-year prediction of incident CVD compared to using a single most recent hs-cTnI measurement. The change process was modelled using a joint (longitudinal and survival) model and compared to a Cox model using a single hs-cTnI measure adjusted for classic CVD risk factors, and evaluated using discrimination statistics. RESULTS: Median hs-cTnI concentrations changed from 2.6 ng/L to 3.4 ng/L over 10 years. The change in hs-cTnI predicts 10-year risk of CVD (581 events); the joint model gave a hazard ratio of 1.31 per interquartile difference in hs-cTnI (95% CI 1.15-1.48) after adjustment for CVD risk factors. However, the joint model performed only marginally better (c-index improvement 0.0041, P = 0.03) than using a single hs-cTnI measure (c-index improvement 0.0052, P = 0.04) for prediction of CVD, compared to a model incorporating CVD risk factors without hs-cTnI (c-index 0.744). CONCLUSIONS: The change in hs-cTnI in 5-year intervals better predicts risk of CVD in the general population, but the most recent measure of hs-cTnI, (at 10 years) is as effective in predicting CVD risk. This simplifies the use of hs-cTnI as a prognostic marker for primary prevention of CVD in the general population.

Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis.

AIMS: Because low-grade inflammation may play a role in the pathogenesis of coronary heart disease (CHD), and pro-inflammatory cytokines govern inflammatory cascades, this study aimed to assess the associations of several pro-inflammatory cytokines and CHD risk in a new prospective study, including meta-analysis of prospective studies. METHODS AND RESULTS: Interleukin-6 (IL-6), IL-18, matrix metalloproteinase-9 (MMP-9), soluble CD40 ligand (sCD40L), and tumour necrosis factor-α (TNF-α) were measured at baseline in a case-cohort study of 1514 participants and 833 incident CHD events within population-based prospective cohorts at the Danish Research Centre for Prevention and Health. Age- and sex-adjusted hazard ratios (HRs) for CHD per 1-SD higher log-transformed baseline levels were: 1.37 (95% CI: 1.21-1.54) for IL-6, 1.26 (1.11-1.44) for IL-18, 1.30 (1.16-1.46) for MMP-9, 1.01 (0.89-1.15) for sCD40L, and 1.13 (1.01-1.27) for TNF-α. Multivariable adjustment for conventional vascular risk factors attenuated the HRs to: 1.26 (1.08-1.46) for IL-6, 1.12 (0.95-1.31) for IL-18, 1.21 (1.05-1.39) for MMP-9, 0.93 (0.78-1.11) for sCD40L, and 1.14 (1.00-1.31) for TNF-α. In meta-analysis of up to 29 population-based prospective studies, adjusted relative risks for non-fatal MI or CHD death per 1-SD higher levels were: 1.25 (1.19-1.32) for IL-6; 1.13 (1.05-1.20) for IL-18; 1.07 (0.97-1.19) for MMP-9; 1.07 (0.95-1.21) for sCD40L; and 1.17 (1.09-1.25) for TNF-α. CONCLUSIONS: Several different pro-inflammatory cytokines are each associated with CHD risk independent of conventional risk factors and in an approximately log-linear manner. The findings lend support to the inflammation hypothesis in vascular disease, but further studies are needed to assess causality.

Repeated measures of body mass index and C-reactive protein in relation to all-cause mortality and cardiovascular disease: results from the consortium on health and ageing network of cohorts in Europe and the United States (CHANCES).

Obesity has been linked with elevated levels of C-reactive protein (CRP), and both have been associated with increased risk of mortality and cardiovascular disease (CVD). Previous studies have used a single 'baseline' measurement and such analyses cannot account for possible changes in these which may lead to a biased estimation of risk. Using four cohorts from CHANCES which had repeated measures in participants 50 years and older, multivariate time-dependent Cox proportional hazards was used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) to examine the relationship between body mass index (BMI) and CRP with all-cause mortality and CVD. Being overweight (≥25-<30 kg/m(2)) or moderately obese (≥30-<35) tended to be associated with a lower risk of mortality compared to normal (≥18.5-<25): ESTHER, HR (95 % CI) 0.69 (0.58-0.82) and 0.78 (0.63-0.97); Rotterdam, 0.86 (0.79-0.94) and 0.80 (0.72-0.89). A similar relationship was found, but only for overweight in Glostrup, HR (95 % CI) 0.88 (0.76-1.02); and moderately obese in Tromsø, HR (95 % CI) 0.79 (0.62-1.01). Associations were not evident between repeated measures of BMI and CVD. Conversely, increasing CRP concentrations, measured on more than one occasion, were associated with an increasing risk of mortality and CVD. Being overweight or moderately obese is associated with a lower risk of mortality, while CRP, independent of BMI, is positively associated with mortality and CVD risk. If inflammation links CRP and BMI, they may participate in distinct/independent pathways. Accounting for independent changes in risk factors over time may be crucial for unveiling their effects on mortality and disease morbidity.

Hospital variation in 30-day mortality after colorectal cancer surgery in denmark: the contribution of hospital volume and patient characteristics.

OBJECTIVE: This study examines variation between hospitals in 30-day mortality after surgery for colorectal cancer (CRC) in Denmark and explores whether hospital volume and patient characteristics contribute to any variation between hospitals. BACKGROUND: Little is known about the variation between hospitals in 30-day mortality after CRC surgery, and the impact of treatment and patient characteristics that might contribute to such variation. METHODS: Hospital variation was quantified using a multilevel approach on data derived from a nationwide database of all adenocarcinomas of colon and rectum diagnosed in Denmark in 2001 to 2004. These data were linked to several central registers providing information on patient's socioeconomic status, comorbidity, and use of medication. In total 11,287 patients, who underwent surgery at any of the 43 surgical departments were included. RESULTS: Hospitals varied from 3.5% to 44.1% in 30-day mortality after emergency colon cancer surgery, and the multilevel analysis showed that emergency patients were 5 times [odd ratio (OR) = 4.6)] as likely to die within 30 days in hospitals with the worst performance compared to those with the best performance. The American Society of Anesthesiologists (ASA) score increased the variation between hospitals (OR = 5.8), whereas the other potential explanatory variables had no effect on the variation. For patients who had elective surgery for colon and rectal cancer the variation in 30-day mortality between hospitals was small and nonsignificant. CONCLUSION: Hospital variation in 30-day mortality after CRC surgery are due to differences in hospitals' ability to take care of emergency patients, especially those with high ASA scores.

Estimating the proportion of Danes at high risk of fatal cardiovascular disease.

AIMS: It has been recommended by several intervention studies to use a high risk approach for cardiovascular disease (CVD) prevention, and the European Guidelines on Cardiovascular Disease Prevention in Clinical Practice (ESC Guidelines) provide a method to identify high risk individuals. Furthermore the ESC Guidelines suggest interventions for the high risk group, with the overall intention to reduce CVD mortality. The ESC Guidelines have not yet been applied in cardiovascular research in Denmark. Therefore, the aim of this study is to estimate the proportion at high risk for fatal CVD in a Danish population. METHODS: Data from a population-based cross-sectional study from the Research Centre for Prevention and Health (the former Glostrup Population Studies) from 2006 was used. A total of 2,815 individuals aged 25-64 years were included in the analysis. The criteria listed in ESC Guidelines were used to identify the high risk group. The results were stratified according to age and sex. RESULTS: A total of 21.2% were categorized as high risk for fatal CVD, and 51.6% of the high risk individuals were categorized due to a SCORE risk ≥ 5%. In general more men than women were categorized as high risk within the different age groups. A larger proportion was categorized in high risk in the oldest age groups compared with the younger ones. CONCLUSIONS: With the considerably large proportion at high risk -one in five individuals - it is worthwhile considering increasing the attention given to identify high risk individuals. Applying the interventions suggested in the ESC Guidelines to high risk individuals could potentially reduce CVD mortality in Denmark.

Prevalence of renal artery stenosis in subjects with moderate hypertension. A population-based study.

AIM: To examine the prevalence of significant renal artery stenosis (RAS) in subjects with moderate to severe hypertension. MATERIALS AND METHODS: Subjects aged 50-66 years with blood pressure >160/100 mmHg or receiving antihypertensive treatment were selected from the population study Inter99. We examined 332 subjects (209 men, 123 women) for RAS >50% of diameter with Doppler-US. Subjects with RAS were re-examined 2 years later. Furthermore, we report sensitivity and specificity of the screening method based on consecutive examinations of 100 patients before referral to renal angiography. RESULTS: The sensitivity and specificity of the Doppler US examination for the detection of RAS was 98% and 96%, respectively. Unilateral RAS was found in 11 subjects. Nine were women. The prevalence of RAS in the examined population was 3.3% (men: 0.9%, women: 7.3%). One patient was referred to balloon angioplasty. Two patients had reduced size and function of the affected kidney. Among the non-invasively treated patients, one showed stenosis progression at the 2-year follow-up examination. CONCLUSION: In subjects aged 50-66 years with hypertension grade II-III, RAS is rare among men, but not among women. These women may suffer from fibromuscular dysplasia. They are at risk of losing kidney function and developing severe hypertension, but they would not have been considered for screening according to present criteria.

Cardiovascular risk estimation tailored to different clinical settings - the Tromsø study.

OBJECTIVE: To develop a cardiovascular risk model simulating different clinical settings using a staged approach. DESIGN: Using data from 27,477 men and women from the Norwegian Tromsø Study in 1986-1987 and 1994-1995, Cox regression models for either myocardial infarction (MI) or stroke combined with a similar model for the competing event a risk model that assess ten-year risk of MI and stroke was developed. Explanatory variables (questions, simple examinations and blood samples) were added gradually. The model was validated using Hosmer-Lemeshow test, the Brier score, c-index, integrated discrimination improvement (IDI) and Net Reclassification Improvement (NRI). RESULTS: In total, 1,298 events of MI and 769 events of stroke were registered. For MI the model showed excellent discrimination in each step with c-index from 0.833 to 0.946. For stroke the c-index ranged between 0.817 and 0.898. IDI showed significant increases in discrimination. The Brier scores and goodness of fit test showed well calibrated models in all steps for all sex- and end-point specific models (p>0.05). CONCLUSIONS: Although the predictive and discriminative ability of the models increased with each step, even the simplest model containing only data from questions or blood samples alone yielded valid estimates of cardiovascular risk.

Cardiovascular risk prediction: Can Systematic Coronary Risk Evaluation (SCORE) be improved by adding simple risk markers? Results from the Copenhagen City Heart Study.

AIM: European society of cardiology (ESC) guidelines recommend that cardiovascular disease (CVD) risk stratification in asymptomatic individuals is based on the Systematic Coronary Risk Evaluation (SCORE) algorithm, which estimates individual 10-year risk of death from CVD. We assessed the potential improvement in CVD risk stratification of 19 easily available risk markers by adding them to the SCORE algorithm. METHODS AND RESULTS: We followed 8476 individuals without prior CVD or diabetes from the Copenhagen City Heart study. The 19 risk markers were: major and minor electrocardiographic (ECG) abnormalities, heart rate, family history (of ischaemic heart disease), body mass index (BMI), waist-hip ratio, walking duration and pace, leisure time physical activity, forced expiratory volume (FEV)1%pred, household income, education, vital exhaustion, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), high-sensitive C-reactive protein (hsCRP) and fibrinogen. With the exception of family history, BMI, triglycerides and minor ECG changes, all risk markers remained significantly associated with CVD mortality after adjustment for SCORE variables. However, the addition of the remaining 15 risk markers resulted in only small changes in discrimination calculated by area under the curve (AUC) and integrated discrimination improvement (IDI) and no improvement in net reclassification improvement (NRI). HsCRP improved AUC by 0.006 (p = 0.015) and IDI by 0.012 (p = 0.002); FEV1%pred improved AUC by 0.006 (p = 0.032) and IDI by 0.006 (p = 0.029). In the intermediate risk group FEV1%pred, education, vital exhaustion and ApoA1 all improved NRI but FEV1%pred was the only risk marker to significantly improve both IDI, AUC and NRI. CONCLUSION: The SCORE algorithm predicted CVD mortality in a Danish cohort well. Despite strong association with CVD mortality, the individual addition of 19 easily available risk makers to the SCORE model resulted in small risk stratification improvements.

Interactions of Lipid Genetic Risk Scores With Estimates of Metabolic Health in a Danish Population.

BACKGROUND: There are several well-established lifestyle factors influencing dyslipidemia and currently; 157 genetic susceptibility loci have been reported to be associated with serum lipid levels at genome-wide statistical significance. However, the interplay between lifestyle risk factors and these susceptibility loci has not been fully elucidated. We tested whether genetic risk scores (GRS) of lipid-associated single nucleotide polymorphisms associate with fasting serum lipid traits and whether the effects are modulated by lifestyle factors or estimates of metabolic health. METHODS AND RESULTS: The single nucleotide polymorphisms were genotyped in 2 Danish cohorts: inter99 (n=5961) for discovery analyses and Health2006 (n=2565) for replication. On the basis of published effect sizes of single nucleotide polymorphisms associated with circulating fasting levels of total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, or triglyceride, 4 weighted GRS were constructed. In a cross-sectional design, we investigated whether the effect of these weighted GRSs on lipid levels were modulated by diet, alcohol consumption, physical activity, and smoking or the individual metabolic health status as estimated from body mass index, waist circumference, and insulin resistance assessed using homeostasis model assessment of insulin resistance. All 4 lipid weighted GRSs associated strongly with their respective trait (from P=3.3×10(-69) to P=1.1×10(-123)). We found interactions between the triglyceride weighted GRS and body mass index and waist circumference on fasting triglyceride levels in Inter99 and replicated these findings in Health2006 (P(interaction)=9.8×10(-5) and 2.0×10(-5), respectively, in combined analysis). CONCLUSIONS: Our findings suggest that individuals who are obese may be more susceptible to the cumulative genetic burden of triglyceride single nucleotide polymorphisms. Therefore, it is suggested that especially these genetically at-risk individuals may benefit more from targeted interventions aiming at obesity prevention.

Distribution of ideal cardiovascular health by educational levels from 1978 to 2006: a time trend study from the capital region of Denmark.

BACKGROUND: The focus on improvements in ideal cardiovascular health is a relatively new approach and to our knowledge nobody has published the trend in regard to educational difference. DESIGN: Time trend analysis from six cross-sectional studies in 1978-2006 from the south-western part of the capital region of Denmark. METHODS: This analysis included 16,935 individuals aged 30-64 years. Ideal cardiovascular health was achieved if all of the following criteria were met: no established cardiovascular disease, no diabetes, no antihypertensive or lipid-lowering treatment, non-smoker, body mass index <25 kg/m(2), blood pressure ≤120/80 mmHg and total cholesterol ≤5 mmol/l. Results are presented adjusted for age and stratified according to sex and educational level as length of vocational training. RESULTS: The proportion of women with ideal cardiovascular health increased from 2% in 1978 to 13% in 2006. From 1991, an educational difference occurred, increasing to a 5-fold difference in 2006 between the highest and lowest educated women. For men, a less pronounced increase occurred from 1% in 1978 to 5% in 2006; a change which was only significant among the highest educated. An educational difference occurred from 1986 to 1999 between the highest and lowest educated men, but was no longer present in 2006. CONCLUSIONS: The trend for women shows an increasing proportion in ideal cardiovascular health with a more unfavourable risk profile among women with a low educational level. For men, the educational difference was less pronounced probably because very few men reached an ideal cardiovascular risk profile. This stresses the importance for preventive efforts targeting low educated groups, and men in particular.

Vitamin D status, liver enzymes, and incident liver disease and mortality: a general population study.

Vitamin D deficiency is common among patients with liver diseases. Both cholestatic and non-cholestatic liver diseases can cause vitamin D deficiency. Whether vitamin D status can also affect liver function is poorly understood. To investigate the association between vitamin D status, liver enzymes, and incident liver disease, we included a total of 2,649 individuals from the Monica10 study conducted in 1993-1994. Vitamin D status as assessed by serum 25-hydroxyvitamin, serum alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transferase (GGT) were measured at baseline. Information on fatal and non-fatal liver disease was obtained from the Danish National Patient Register and The Danish Registry of Causes of Death, respectively. Median follow-up time was 16.5 years, and there were 62 incident cases of fatal and non-fatal liver disease. Multivariable Cox regression analyses with age as underlying time axis and delayed entry showed a statistically significant inverse association between vitamin D status and incident liver disease with a hazard ratio = 0.88 (95 % confidence interval 0.79-0.99) per 10 nmol/l higher vitamin D status at baseline (adjusted for gender, season, alcohol consumption, smoking, physical activity, dietary habits, education, body mass index, and ALT). The risk of having a high level of ALT, AST, or GGT tended to be higher for lower vitamin D levels, although not statistically significant. In this general population study, vitamin D status was inversely associated with incident liver disease. Further studies are needed to determine whether patients in risk of developing impaired liver function should be screened for vitamin D deficiency for preventive purposes.

The contribution of educational class in improving accuracy of cardiovascular risk prediction across European regions: The MORGAM Project Cohort Component.

OBJECTIVE: To assess whether educational class, an index of socioeconomic position, improves the accuracy of the SCORE cardiovascular disease (CVD) risk prediction equation. METHODS: In a pooled analysis of 68 455 40-64-year-old men and women, free from coronary heart disease at baseline, from 47 prospective population-based cohorts from Nordic countries (Finland, Denmark, Sweden), the UK (Northern Ireland, Scotland), Central Europe (France, Germany, Italy) and Eastern Europe (Lithuania, Poland) and Russia, we assessed improvements in discrimination and in risk classification (net reclassification improvement (NRI)) when education was added to models including the SCORE risk equation. RESULTS: The lowest educational class was associated with higher CVD mortality in men (pooled age-adjusted HR=1.64, 95% CI 1.42 to 1.90) and women (HR=1.31, 1.02 to 1.68). In men, the HRs ranged from 1.3 (Central Europe) to 2.1 (Eastern Europe and Russia). After adjustment for the SCORE risk, the association remained statistically significant overall, in the UK and Eastern Europe and Russia. Education significantly improved discrimination in all European regions and classification in Nordic countries (clinical NRI=5.3%) and in Eastern Europe and Russia (NRI=24.7%). In women, after SCORE risk adjustment, the association was not statistically significant, but the reduced number of deaths plays a major role, and the addition of education led to improvements in discrimination and classification in the Nordic countries only. CONCLUSIONS: We recommend the inclusion of education in SCORE CVD risk equation in men, particularly in Nordic and East European countries, to improve social equity in primary prevention. Weaker evidence for women warrants the need for further investigations.

Impact of age and gender on the prevalence and prognostic importance of the metabolic syndrome and its components in Europeans. The MORGAM Prospective Cohort Project.

OBJECTIVE: To investigate the influence of age and gender on the prevalence and cardiovascular disease (CVD) risk in Europeans presenting with the Metabolic Syndrome (MetS). METHODS: Using 36 cohorts from the MORGAM-Project with baseline between 1982-1997, 69094 men and women aged 19-78 years, without known CVD, were included. During 12.2 years of follow-up, 3.7%/2.1% of men/women died due to CVD. The corresponding percentages for fatal and nonfatal coronary heart disease (CHD) and stroke were 8.3/3.8 and 3.1/2.5. RESULTS: The prevalence of MetS, according to modified definitions of the International Diabetes Federation (IDF) and the revised National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII), increased across age groups for both genders (P<0.0001); with a 5-fold increase in women from ages 19-39 years to 60-78 years (7.4%/7.6% to 35.4%/37.6% for IDF/NCEP-ATPIII) and a 2-fold increase in men (5.3%/10.5% to 11.5%/21.8%). Using multivariate-adjusted Cox regressions, the associations between MetS and all three CVD events were significant (P<0.0001). For IDF/NCEP-ATPIII in men and women, hazard ratio (HR) for CHD was 1.60/1.62 and 1.93/2.03, for CVD mortality 1.73/1.65 and 1.77/2.06, and for stroke 1.51/1.53 and 1.58/1.77. Whereas in men the HRs for CVD events were independent of age (MetS*age, P>0.05), in women the HRs for CHD declined with age (HRs 3.23/3.98 to 1.55/1.56; MetS*age, P=0.01/P=0.001 for IDF/NCEP-ATPIII) while the HRs for stroke tended to increase (HRs 1.31/1.25 to 1.55/1.83; MetS*age, P>0.05). CONCLUSION: In Europeans, both age and gender influenced the prevalence of MetS and its prognostic significance. The present results emphasise the importance of being critical of MetS in its current form as a marker of CVD especially in women, and advocate for a redefinition of MetS taking into account age especially in women.

Do other cardiovascular risk factors influence the impact of age on the association between blood pressure and mortality? The MORGAM Project.

OBJECTIVE: To investigate age-related shifts in the relative importance of SBP and DBP as predictors of cardiovascular mortality and all-cause mortality and whether these relations are influenced by other cardiovascular risk factors. METHODS: Using 42 cohorts from the MORGAM Project with baseline between 1982 and 1997, 85 772 apparently healthy Europeans and Australians aged 19-78 years were included. During 13.3 years of follow-up, 9.2% died (of whom 7.2% died due to stroke and 21.1% due to coronary heart disease, CHD). RESULTS: Mortality risk was analyzed using hazard ratios per 10-mmHg/5-mmHg increase in SBP/DBP by multivariate-adjusted Cox regressions, including SBP and DBP simultaneously. Because of nonlinearity, SBP and DBP were analyzed separately for blood pressure (BP) values above and below a cut-point wherein mortality risk was the lowest. For the total population, significantly positive associations were found between stroke mortality and SBP [hazard ratio = 1.19 (1.13-1.25)] and DBP at least 78 mmHg [hazard ratio = 1.08 (1.02-1.14)], CHD mortality and SBP at least 116 mmHg [1.20 (1.16-1.24)], and all-cause mortality and SBP at least 120 mmHg [1.09 (1.08-1.11)] and DBP at least 82 mmHg [1.03 (1.02-1.05)]. BP values below the cut-points were inversely related to mortality risk. Taking into account the age × BP interaction, there was a gradual shift from DBP (19-26 years) to both DBP and SBP (27-62 years) and to SBP (63-78 years) as risk factors for stroke mortality and all-cause mortality, but not CHD mortality. The age at which the importance of SBP exceeded DBP was for stroke mortality influenced by sex, cholesterol, and country risk. CONCLUSION: Age-related shifts to the superiority of SBP exist for stroke mortality and all-cause mortality, and for stroke mortality was this shift influenced by other cardiovascular risk factors.

Seasonality of cardiovascular risk factors: an analysis including over 230†000 participants in 15 countries.

OBJECTIVE: To assess the seasonality of cardiovascular risk factors (CVRF) in a large set of population-based studies. METHODS: Cross-sectional data from 24 population-based studies from 15 countries, with a total sample size of 237 979 subjects. CVRFs included Body Mass Index (BMI) and waist circumference; systolic (SBP) and diastolic (DBP) blood pressure; total, high (HDL) and low (LDL) density lipoprotein cholesterol; triglycerides and glucose levels. Within each study, all data were adjusted for age, gender and current smoking. For blood pressure, lipids and glucose levels, further adjustments on BMI and drug treatment were performed. RESULTS: In the Northern and Southern Hemispheres, CVRFs levels tended to be higher in winter and lower in summer months. These patterns were observed for most studies. In the Northern Hemisphere, the estimated seasonal variations were 0.26 kg/m(2) for BMI, 0.6 cm for waist circumference, 2.9 mm Hg for SBP, 1.4 mm Hg for DBP, 0.02 mmol/L for triglycerides, 0.10 mmol/L for total cholesterol, 0.01 mmol/L for HDL cholesterol, 0.11 mmol/L for LDL cholesterol, and 0.07 mmol/L for glycaemia. Similar results were obtained when the analysis was restricted to studies collecting fasting blood samples. Similar seasonal variations were found for most CVRFs in the Southern Hemisphere, with the exception of waist circumference, HDL, and LDL cholesterol. CONCLUSIONS: CVRFs show a seasonal pattern characterised by higher levels in winter, and lower levels in summer. This pattern could contribute to the seasonality of CV mortality.

Need to combine individual strategies with population-level strategies in the prevention of coronary heart disease.

INTRODUCTION: The aim of this paper was to examine the relation between the distribution of risk, the distribution of coronary heart disease (CHD) events and the proportion who develop CHD according to risk. MATERIAL AND METHODS: Baseline data from a cross-sectional study conducted in 1999-2001 comprising information on systolic blood pressure, low density lipoprotein cholesterol and a multifactor risk score, The Copenhagen Risk Score, were related to ten years of fatal and non-fatal events of CHD in 6,784 participants. RESULTS: The results were unambiguous regarding all three examined parameters. They showed that the majority of all fatal and non-fatal events of CHD occur within the large group of the population which is at low or no risk of CHD. DISCUSSION: The three determinants in relation to CHD events indicate that changing the risk of a whole population through widespread comprehensive societal policies may be more efficient than medical treatment and health counselling targeting persons already at high-risk, which will be of benefit for the individual persons only. FUNDING: Funding was received from The Health Insurance Foundation (grant number 2010 B 131). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Poor predictive ability of the risk chart SCORE in a Danish population.

INTRODUCTION: In Denmark, the European risk chart Systematic COronary Risk Evaluation (SCORE) from the European Society of Cardiology is recommended for use in cardiovascular prevention. Nevertheless, its predictive ability in a Danish population has never been investigated. The purpose of this study was therefore to assess the predictive ability of the SCORE risk chart with regard to fatal cardiovascular risk according to the socio-demographic factors of age, sex, income and education in a Danish population. MATERIAL AND METHODS: Data from the third Copenhagen City Heart Study (n = 4,224) were linked to the Danish Cause of Death Registry. Calibration (i.e. Hosmer-Lemeshow goodness-of-fit), expected-to-observed (E/O) mortality ratios in the total population and for subgroups, as well as discrimination (i.e. sensitivity, specificity, Area Under the Receiver Operator Characteristic (AUROC) and predictive values) were tested. Both SCORE high-risk and low-risk were applied for comparison. RESULTS: The results showed that both SCORE high-risk and low-risk performed acceptably in terms of discrimination (AUROC ≈ 0.7-0.8); however, calibration for both SCORE charts was inadequate (χ2 > 20; p < 0.001). E/O-ratios varied with age, sex and socioeconomic status. CONCLUSION: There is a need to recalibrate SCORE to risk levels and risk factor distribution in the Danish population. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Genetic risk score of 46 type 2 diabetes risk variants associates with changes in plasma glucose and estimates of pancreatic ß-cell function over 5 years of follow-up.

More than 40 genetic risk variants for type 2 diabetes have been validated. We aimed to test whether a genetic risk score associates with the incidence of type 2 diabetes and with 5-year changes in glycemic traits and whether the effects were modulated by changes in BMI and lifestyle. The Inter99 study population was genotyped for 46 variants, and a genetic risk score was constructed. During a median follow-up of 11 years, 327 of 5,850 individuals developed diabetes. Physical examinations and oral glucose tolerance tests were performed at baseline and after 5 years (n = 3,727). The risk of incident type 2 diabetes was increased with a hazard ratio of 1.06 (95% CI 1.03-1.08) per risk allele. While the population in general had improved glucose regulation during the 5-year follow-up period, each additional allele in the genetic risk score was associated with a relative increase in fasting, 30-min, and 120-min plasma glucose values and a relative decrease in measures of ß-cell function over the 5-year period, whereas indices of insulin sensitivity were unaffected. The effect of the genetic risk score on 5-year changes in fasting plasma glucose was stronger in individuals who increased their BMI. In conclusion, a genetic risk score based on 46 variants associated strongly with incident type 2 diabetes and 5-year changes in plasma glucose and ß-cell function. Individuals who gain weight may be more susceptible to the cumulative impact of type 2 diabetes risk variants on fasting plasma glucose.

Genetic variant SLC2A2 [corrected] Is associated with risk of cardiovascular disease ­ assessing the individual and cumulative effect of 46 type 2 diabetes related genetic variants.

AIM: To assess the individual and combined effect of 46 type 2 diabetes related risk alleles on incidence of a composite CVD endpoint. METHODS: Data from the first Danish MONICA study (N = 3523) and the Inter99 study (N = 6049) was used. Using Cox proportional hazard regression the individual effect of each risk allele on incident CVD was analyzed. Risk was presented as hazard ratios (HR) per risk allele. RESULTS: During 80,859 person years 1441 incident cases of CVD (fatal and non-fatal) occurred in the MONICA study. In Inter99 942 incident cases were observed during 61,239 person years. In the Danish MONICA study four gene variants were significantly associated with incident CVD independently of known diabetes status at baseline; SLC2A2 rs11920090 (HR 1.147, 95% CI 1.027-1.283 , P = 0.0154), C2CD4A rs7172432 (1.112, 1.027-1.205 , P = 0.0089), GCKR rs780094 (1.094, 1.007-1.188 , P = 0.0335) and C2CD4B rs11071657 (1.092, 1.007-1.183 , P = 0.0323). The genetic score was significantly associated with increased risk of CVD (1.025, 1.010-1.041, P = 0.0016). In Inter99 two gene variants were associated with risk of CVD independently of diabetes; SLC2A2 (HR 1.180, 95% CI 1.038-1.341 P = 0.0116) and FTO (0.909, 0.827-0.998, P = 0.0463). Analysing the two populations together we found SLC2A2 rs11920090 (HR 1.164, 95% CI 1.070-1.267, P = 0.0004) meeting the Bonferroni corrected threshold for significance. GCKR rs780094 (1.076, 1.010-1.146, P = 0.0229), C2CD4B rs11071657 (1.067, 1.003-1.135, P = 0.0385) and NOTCH2 rs10923931 (1.104 (1.001 ; 1.217 , P = 0.0481) were found associated with CVD without meeting the corrected threshold. The genetic score was significantly associated with increased risk of CVD (1.018, 1.006-1.031, P = 0.0043). CONCLUSIONS: This study showed that out of the 46 genetic variants examined only the minor risk allele of SLC2A2 rs11920090 was significantly (P = 0.0005) associated with a composite endpoint of incident CVD below the threshold for statistical significance corrected for multiple testing. This potential pathway needs further exploration.

Impact of age on the importance of systolic and diastolic blood pressures for stroke risk: the MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) Project.

This study investigates age-related shifts in the relative importance of systolic (SBP) and diastolic (DBP) blood pressures as predictors of stroke and whether these relations are influenced by other cardiovascular risk factors. Using 34 European cohorts from the MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) Project with baseline between 1982 and 1997, 68 551 subjects aged 19 to 78 years, without cardiovascular disease and not receiving antihypertensive treatment, were included. During a mean of 13.2 years of follow-up, stroke incidence was 2.8%. Stroke risk was analyzed using hazard ratios per 10-mm Hg/5-mm Hg increase in SBP/DBP by multivariate-adjusted Cox regressions, including SBP and DBP simultaneously. Because of nonlinearity, DBP was analyzed separately for DBP ≥ 71 mm Hg and DBP <71 mm Hg. Stroke risk was associated positively with SBP and DBP ≥ 71 mm Hg (SBP/DBP ≥ 71 mm Hg; hazard ratios: 1.15/1.06 [95% CI: 1.12-1.18/1.03-1.09]) and negatively with DBP <71 mm Hg (0.88[0.79-0.98]). The hazard ratio for DBP decreased with age (P<0.001) and was not influenced by other cardiovascular risk factors. Taking into account the age × DBP interaction, both SBP and DBP ≥ 71 mm Hg were significantly associated with stroke risk until age 62 years, but in subjects older than 46 years the superiority of SBP for stroke risk exceeded that of DBP ≥ 71 mm Hg and remained significant until age 78 years. DBP <71 mm Hg became significant at age 50 years with an inverse relation to stroke risk. In Europeans, stroke risk should be assessed by both SBP and DBP until age 62 years with increased focus on SBP from age 47 years. From age 62 years, emphasis should be on SBP without neglecting the potential harm of very low DBP.