MOnica Risk, Genetics, Archiving And Monograph Research Articles

Biomarker-based prediction of fatal and non-fatal cardiovascular outcomes in individuals of the general population with and without diabetes mellitus

Abstract Introduction Cardiovascular biomarkers may reflect different aspects of cardiovascular disease, including myocardial tissue damage (high-sensitive cardiac troponin [hs-cTn]), hemodynamic stress (N-terminal prohormone of brain natriuretic peptide [NT-proBNP)), or inflammation (high-sensitivity C-reactive protein [hs-CRP]). Purpose To determine the risk for fatal and non-fatal cardiovascular events in patients with diabetes mellitus (DM), a high-risk group for cardiovascular complications, after accounting for these biomarkers and to determine the risk associated with these biomarkers. Methods Harmonized data of population-based studies from the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomaCaRE) and MOnica Risk, Genetics, Archiving and Monograph (MORGAM) consortia were used to calculate hazard ratios (HRs, 95% confidence intervals [CI] per standard deviation) for these biomarkers adjusted for diabetes, patient characteristics and biomarkers for their association with the primary endpoint of fatal and non-fatal cardiovascular events during a median follow-up of 9.6 years (maximum 28 years). Additionally, a years-of-life-lost analysis was conducted stratified by prevalent diabetes and specific biomarker cut-offs known to be associated with increased risk for events (hs-cTnI >5 ng/L, NTproBNP >125 ng/L, hs-CRP >5mg/L). Results We included 95,302 individuals, of whom 6,501 had DM (6.8%). Cox-regression analysis revealed DM to be independently associated with the primary endpoint (2.1 [95% CI 1.9, 2.3], p<0.001) despite adjustment for clinical characteristics and biomarkers. Also, all three biomarkers were independent predictors themselves: log-transformed NT-proBNP 1.3 [95% CI 1.3, 1.4] p<0.001; log-transformed hs-CRP 1.2 [95% CI 1.1, 1.2] p<0.001; third-root-transformed hs-cTnI 1.1 [95% CI 1.0, 1.1] p=0.0038). The sex-, age- and cohort-adjusted HR for the primary endpoint according to absolute biomarker concentrations derived by cox-regression models using cubic splines is provided for the three biomarkers in Figure 1. Upon dichotomization of biomarkers, individuals with diabetes and at least one elevated biomarker lost a median of 15.5 healthy years because of the primary endpoint (Kaplan-Meier plot in Figure 2, with age on the x-axis). Conclusion Our findings confirm that diabetes confers a residual cardiovascular risk beyond adjustment for clinical characteristics and cardiovascular biomarker. Furthermore, biomarkers may aid in the identification of patients at highest risk, which should be considered in future models of risk prediction. Funding Acknowledgement Type of funding sources: None.

Alcohol intake and total mortality in 142 960 individuals from the MORGAM Project: a population-based study.

To test the association of alcohol consumption with total and cause-specific mortality risk. Prospective observational multi-centre population-based study. Sixteen cohorts (15 from Europe) in the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) Project. A total of 142 960 individuals (mean age 50±13 years, 53.9% men). Average alcohol intake by food frequency questionnaire, total and cause-specific mortality. In comparison with life-time abstainers, consumption of alcohol less than 10 g/day was associated with an average 11% [95% confidence interval (CI)=7-14%] reduction in the risk of total mortality, while intake >20 g/day was associated with a 13% (95% CI=7-20%) increase in the risk of total mortality. Comparable findings were observed for cardiovascular (CV) deaths. With regard to cancer, drinking up to 10 g/day was not associated with either mortality risk reduction or increase, while alcohol intake >20 g/day was associated with a 22% (95% CI=10-35%) increased risk of mortality. The association of alcohol with fatal outcomes was similar in men and women, differed somewhat between countries and was more apparent in individuals preferring wine, suggesting that benefits may not be due to ethanol but other ingredients. Mediation analysis showed that high-density lipoprotein cholesterol explained 2.9 and 18.7% of the association between low alcohol intake and total as well as CV mortality, respectively. In comparison with life-time abstainers, consuming less than one drink per day (nadir at 5 g/day) was associated with a reduced risk of total, cardiovascular and other causes mortality, except cancer. Intake of more than two drinks per day was associated with an increased risk of total, cardiovascular and especially cancer mortality.

Simple cardiovascular risk stratification using anthropometric measures instead of serum cholesterol. The MORGAM Prospective Cohort Project

Abstract Background Body composition predicts cardiovascular outcomes, but it is uncertain whether anthropometric measures can replace the more expensive serum total cholesterol for cardiovascular risk stratification in low resource settings. Purpose The purpose of the study was to compare the additive prognostic ability of serum total cholesterol with that of body mass index (BMI), waist/hip ratio (WHR), and estimated fat mass (EFM, calculated using a validated prediction equation), individually and combined. Methods We used data from the MORGAM (MONICA, Risk, Genetics, Archiving, and Monograph) Prospective Cohort Project, an international pooling of cardiovascular cohorts, to determine the relationship between anthropometric measures, serum cholesterol, and cardiovascular events, using multivariable Cox proportional-hazards regression analysis. We further investigated the ability of these measures to enhance prognostication beyond a simpler prediction model, consisting of age, sex, smoking status, systolic blood pressures, and country, using comparison of area under the receiver operating characteristics curve (AUCROC) derived from binary logistic regression models. The primary endpoint was major adverse cardiovascular events (MACE), defined as a composite of death from coronary heart disease, myocardial infarction, or stroke. Results The study population consisted of 52,188 apparently healthy subjects (56.3% men) aged 47±12 years ranging from 20 to 84, derived from 37 European cohorts, with baseline between 1982–2002 all followed for 10 years during which MACE occurred in 2465 (4.7%) subjects. All anthropometric measures (BMI: hazard ratio (HR) 1.04 [95% confidence interval (CI): 1.03–1.05] per kg/m2; WHR: HR 7.5 [4.0–14.0] per unit; EFM: HR 1.02 [1.01–1.02] per kg) as well as serum total cholesterol (HR 1.20 [1.16–1.24] per mmol/l) were significantly associated with MACE (P<0.001 for all), independently of age, sex, smoking status, systolic blood pressures, and country. The addition of serum cholesterol significantly improved the predictive ability of the simple model (AUCROC 0.818 vs. 0.814, P<0.001), as did the combination of WHR, BMI, and EFM (AUCROC 0.817 vs. 0.814, P=0.004). When assessed individually, BMI (AUCROC 0.816 vs. 0.814, P=0.004) and WHR (AUCROC 0.815 vs. 0.814, P=0.02) improved model performance, while EFM narrowly missed significance (AUCROC 0.815 vs. 0.814, P=0.06). There was no significant difference in the predictive ability of a model including serum cholesterol versus that including all three anthropometric measures (AUCROC 0.818 vs. 0.817, P=0.13). The figure shows the pertinent areas under the ROC curve in predicting MACE. Conclusion In this large population-based cohort study, the addition of a combination of anthropometric measures, i.e. BMI, WHR, and EFM, raised the predictive ability of a simple prognostic model comparable to that obtained by the addition of serum total cholesterol. Figure 1 Funding Acknowledgement Type of funding source: None

Combined Influence of Waist and Hip Circumference on Risk of Death in a Large Cohort of European and Australian Adults.

BackgroundWaist circumference and hip circumference are both strongly associated with risk of death; however, their joint association has rarely been investigated.Methods and ResultsThe MONICA Risk, Genetics, Archiving, and Monograph (MORGAM) Project was conducted in 30 cohorts from 11 countries; 90 487 men and women, aged 30 to 74 years, predominantly white, with no history of cardiovascular disease, were recruited in 1986 to 2010 and followed up for up to 24 years. Hazard ratios were estimated using sex‐specific Cox models, stratified by cohort, with age as the time scale. Models included baseline categorical obesity measures, age, total and high‐density lipoprotein cholesterol, systolic blood pressure, antihypertensive drugs, smoking, and diabetes mellitus. A total of 9105 all‐cause deaths were recorded during a median follow‐up of 10 years. Hazard ratios for all‐cause death presented J‐ or U‐shaped associations with most obesity measures. With waist and hip circumference included in the same model, for all hip sizes, having a smaller waist was strongly associated with lower risk of death, except for men with the smallest hips. In addition, among those with smaller waists, hip size was strongly negatively associated with risk of death, with ≈20% more people identified as being at increased risk compared with waist circumference alone.ConclusionsA more complex relationship between hip circumference, waist circumference, and risk of death is revealed when both measures are considered simultaneously. This is particularly true for individuals with smaller waists, where having larger hips was protective. Considering both waist and hip circumference in the clinical setting could help to best identify those at increased risk of death.

Abstract P227: Association of Alcohol Intake with Cardiovascular and Total Mortality

Introduction: Moderate alcohol intake is associated with reduced risk of ischemic heart disease and total mortality but might have a detrimental role in several other diseases (in particular some cancers). The association of moderate alcohol intake with reduced total mortality has therefore been questioned. Hypothesis: Alcohol intake have a non-linear association with cardiovascular (CV) and total mortality. Methods: Using harmonised data from the cohorts in the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) Project, the association of alcohol intake with risk of cardiovascular disease and total mortality was assessed using multivariable Cox regression. Multiple imputation (n=10) was used to accommodate missing data for covariates. Results: 67.4% of the populations studied were drinkers (median intake among drinkers 11 g/day of ethanol, no missing data). Their mortality was observed over median follow-up of 13.8 yrs and covariates (age, sex, smoking, hypertension, diabetes, history of CVD, BMI and level of education) were available for 19 cohorts (1 from Australia and 18 from Europe), including 197,113 individuals (mean age 51±12 y, 60% men, no missing data) and 36,730 deaths (12,644 coronary or cerebrovascular). Former drinkers (2.8%) were excluded from the reference group, which thus comprised habitual teetotallers only (17.7%). Because of missing data, we failed to distinguish between teetotallers and former drinkers in n=24,036 (12.2%) non-drinkers; these individuals were analysed separately but not included in the reference group. In comparison with the reference group, intake of alcohol up to 5 g/day was associated with a 10.5% (95%CI: 6.7% to 14.2%) reduction in the risk of total mortality and 11.8% (5.2% to 17.9%) in the risk of CV mortality; intake between 5 and 10 g/day with a 6.5% (2.0% to 11.0%) and a 3.4% (0.3% to 15.5%) reduction, respectively, while intake over 20 g/day was associated with a 14.5% (9.6% to 19.7%) increase in risk of total mortality and a 6.3% (-1.5% to 14.7%) rise in the risk of CV mortality. Findings were similar in men and women and according to level of education, whereas they were heterogeneous across Countries, with greater protection by alcohol observed in Italy and France and lowest in Australia. The reduced risk of mortality associated with alcohol in moderation was more marked when the beverage of preference was wine rather than beer or spirits; the increased risk associated with heavy intake appeared in individuals whose beverage of preference was beer or spirits. Conclusions: Using a large multi Country cohort, we confirmed that intake of more than 2 alcoholic units per day is associated with a detrimental health effect, while intake of alcohol in moderation (up to 1 unit per day) is associated with reduced risk of CV and total mortality, with small variations according to Country and type of alcoholic beverage.

Determinants of social inequalities in stroke incidence across Europe: a collaborative analysis of 126 635 individuals from 48 cohort studies

BackgroundKnowledge on the origins of the social gradient in stroke incidence in different populations is limited. This study aims to estimate the burden of educational class inequalities in stroke incidence...

Educational class inequalities in the incidence of coronary heart disease in Europe

ObjectiveTo estimate the burden of social inequalities in coronary heart disease (CHD) and to identify their major determinants in 15 European populations.MethodsThe MORGAM (MOnica Risk, Genetics, Archiving and Monograph) study...

Ischemic stroke is associated with the ABO locus: the EuroCLOT study.

ObjectiveEnd-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy REFVIDunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.MethodsCommon genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).ResultsStage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10–8) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10–186), rs10665 with FVII (p = 2.4 × 10–47), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10–57) and factor VIII (p = 1.2 × 10–36). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88–0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).InterpretationABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype. Ann Neurol 2013

Impact of Age on the Importance of Systolic and Diastolic Blood Pressures for Stroke Risk

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 &lt;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 &lt;71 mm Hg (0.88[0.79–0.98]). The hazard ratio for DBP decreased with age (P&lt;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 &lt;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.

Measures of Abdominal Adiposity and the Risk of Stroke

Excess fat accumulates in the subcutaneous and visceral adipose tissue compartments. We tested the hypothesis that indicators of visceral adiposity, namely, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR), are better predictors of stroke risk than body mass index (BMI). The association of BMI, WC, WHR, and WHtR with stroke was assessed in 31,201 men and 23,516 women, free of vascular disease at baseline, from the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) study. During a mean follow-up of 11 years, 1130 strokes were recorded. Relative risks (95% CI) were calculated by Cox regression after stratification for center and adjustment for age, smoking, educational level, alcohol consumption, hypertension, diabetes, total cholesterol, high-density lipoprotein cholesterol, and BMI and model fit was assessed using log-likelihoods. BMI, WC, WHR, and WHtR were associated with the risk of stroke in men. After full adjustment including BMI, the relative risks for stroke remained significant for WC (1.19 [1.02 to 1.34] per 1 SD increase in WC), WHR (1.14 [1.03 to 1.26]), and WHtR (1.50 [1.28 to 1.77]). Among women, the extent of the associations with stroke risk was similar for WHtR (1.31 [1.04 to 1.65]), WC (1.19 [0.96 to 1.47]), and WHR (1.08 [0.97 to 1.22]). Further analyses by World Health Organization obesity categories showed that WC, WHR, and WHtR were associated with the risk of stroke also in lean men and women (BMI<25 kg/m2), independently of confounders, cardiovascular risk factors, and BMI. Indicators of abdominal adiposity, especially WHtR, are more strongly associated with stroke risk than BMI. These results emphasize the importance of measuring abdominal adiposity, especially in lean subjects.

How Do We Find the Best Biomarkers for Cardiovascular Disease?

Conventional cardiovascular risk assessment is based on traditional risk factors such as serum cholesterol concentrations (cholesterol, HDL cholesterol, LDL cholesterol) and blood pressure levels. It is becoming increasingly clear that the newer laboratory measures may help to refine risk estimates in the general population. In a recent publication of the MONICA5 (Monitoring of Trends and Determinants of Cardiovascular Disease) investigators 1, Blankenberg and colleagues evaluated the potential contribution of 30 novel biomarkers to the 10-year cardiovascular disease risk in 2 population cohorts. These biomarkers were part of the MORGAM (MONICA, Risk, Genetics, Archiving, and Monograph) Biomarker Project and were representative of 9 distinct metabolic processes linked to atherosclerosis 2. They include ( a ) lipid-related biomarkers, ( b ) renal function markers, ( c ) metabolic markers representing glucose and obesity pathways, ( d ) markers of vascular function and neurohumoral activity, ( e ) inflammation markers, ( f ) markers of oxidative stress and antioxidants, ( g ) coagulation markers, ( h ) angiogenesis markers, and ( i ) necrosis markers. In addition to the inclusion of a large number of biomarkers for assessment, this study was based on a highly standardized and comprehensive quality control and assurance program implemented on clinical laboratory instruments. All analyses were …

Stroke risk estimation across nine European countries in the MORGAM project

BackgroundPrevious tools for stroke risk assessment have either been developed for specific populations or lack data on non-fatal events or uniform data collection. The purpose of this study was to...

Relative Risks for Stroke by Age, Sex, and Population Based on Follow-Up of 18 European Populations in the MORGAM Project

Within the framework of the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) Project, the variations in impact of classical risk factors of stroke by population, sex, and age were analyzed. Follow-up data were collected in 43 cohorts in 18 populations in 8 European countries surveyed for cardiovascular risk factors. In 93 695 persons aged 19 to 77 years and free of major cardiovascular disease at baseline, total observation years were 1 234 252 and the number of stroke events analyzed was 3142. Hazard ratios were calculated by Cox regression analyses. Each year of age increased the risk of stroke (fatal and nonfatal together) by 9% (95% CI, 9% to 10%) in men and by 10% (9% to 10%) in women. A 10-mm Hg increase in systolic blood pressure involved a similar increase in risk in men (28%; 24% to 32%) and women (25%; 20% to 29%). Smoking conferred a similar excess risk in women (104%; 78% to 133%) and in men (82%; 66% to 100%). The effect of increasing body mass index was very modest. Higher high-density lipoprotein cholesterol levels decreased the risk of stroke more in women (hazard ratio per mmol/L 0.58; 0.49 to 0.68) than in men (0.80; 0.69 to 0.92). The impact of the individual risk factors differed somewhat between countries/regions with high blood pressure being particularly important in central Europe (Poland and Lithuania). Age, sex, and region-specific estimates of relative risks for stroke conferred by classical risk factors in various regions of Europe are provided. From a public health perspective, an important lesson is that smoking confers a high risk for stroke across Europe.