EPIC-Norfolk Prospective Population Study Research Articles

Tryptophan metabolites and incident cardiovascular disease: The EPIC-Norfolk prospective population study

Background and aimsCardiovascular disease (CVD) remains the largest cause of death globally due to various risk factors. One novel potential contributor to CVD might be the metabolism of the essential amino acid tryptophan (Trp), which through many pathways can produce immunomodulatory metabolites such as kynurenine, indole-3-propionate and serotonin. We aim to identify the metabolites with the strongest association with cardiovascular disease, utilizing a substantial and diverse cohort of individuals. In our pursuit of this aim, our primary focus is to validate and reinforce the findings from previous cross-sectional studies. MethodsWe used the community-based EPIC-Norfolk cohort (46.3 % men, age 59.8 ± 9.0) with a median follow-up of 22.1 (17.6–23.3) years to study associations between the relative levels of Trp metabolites measured with untargeted metabolomics and incident development of CVD. Serum from n = 11,972 apparently healthy subjects was analysed, of which 6982 individuals had developed CVD at the end of follow-up. Cox proportional hazard models were used to study associations, adjusted for sex, age, conventional cardiovascular risk factors and CRP. All metabolites were Ln-normalised prior to analysis. ResultsHigher levels of Trp were inversely associated with mortality (HR 0.73; CI 0.64–0.83) and fatal CVD (HR 0.76; CI 0.59–0.99). Higher levels of kynurenine (HR 1.33; CI 1.19–1.49) and the [Kynurenine]/[Tryptophan]-ratio (HR 1.24; CI 1.14–1.35) were associated with a higher incident development of CVD. Serotonin was not associated with overall CVD, but we did find associations for myocardial infarction and stroke. Adjustment for CRP did not yield any discernible differences in effect size. ConclusionsTryptophan levels were inversely correlated with CVD, while several of its major metabolites (especially kynurenine and serotonin) were positively correlated. These findings indicate that mechanistic studies are required to understand the role of Trp metabolism in CVD with the goal to identify new therapeutic targets.

Tryptophan metabolites and incident cardiovascular disease in the EPIC-Norfolk prospective population study

Tryptophan metabolites and incident cardiovascular disease in the EPIC-Norfolk prospective population study

Performance of the Systematic COronary Risk Evaluation 2 (SCORE2) in the EPIC-Norfolk prospective population study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): EPIC-Norfolk is supported by programme grants from the Medical Research Council UK (MRC G0401527, MRC G0701863, MRC G1000143) and Cancer Research UK (CRUK 8257). Introduction The latest European guidelines recommend the use of the Systematic COronary Risk Evaluation 2 (SCORE2) to assess 10-year risk of fatal and non-fatal cardiovascular disease (CVD) in individuals aged 40-70 years. Therefore, validation of the SCORE2 algorithm in a large population is needed. Purpose To assess the predictive performance of SCORE2 in individuals without prior myocardial infarction, stroke or diabetes mellitus. Methods Individuals aged 40-70 without prior myocardial infarction, stroke or diabetes mellitus were included from the European Prospective Investigation of Cancer Norfolk (EPIC-Norfolk) prospective population cohort. We assessed discriminative power using the C-statistic; calibration was assessed by plotting calculated SCORE2 (low-risk algorithm) 10-year risks against observed CVD event rates. We defined the composite cardiovascular outcome as death due to ischemic heart disease, cardiac failure, cerebrovascular disease or peripheral-artery disease, or non-fatal myocardial infarction or non-fatal stroke. Observed probabilities were adjusted for competing mortality events. Results We included 20,318 individuals (56% women) with a median (IQR) age of 56 (50-63) years, with baseline measures between 1993-1997. Mean predicted 10-year risk was 3.7% (95% confidence interval (CI) 3.7-3.8) versus adjusted observed 4.2% (95% CI 3.9-4.5) 10-year CVD incidence, yielding a ratio of 1.1 (95% CI 1.1-1.2).(Figure) Observed events consisted of 1.5% (95% CI 1.3-1.7) fatal CVD events, 1.8% (95% CI 1.6-2.0) non-fatal myocardial infarctions, 1.5% (95% CI 1.3-1.6) non-fatal strokes and 23.4% (95% CI 22.1-23.2) competing mortality events. Overall C-statistic was 0.75 (95% CI 0.73-0.77). Conclusion SCORE2 demonstrates reasonable discriminative ability and accurate risk estimations in low-risk individuals in a large, prospective population cohort. However, as actual CVD incidence is expected to be lower given the baseline between 1993-1997, these findings do not indicate that SCORE2 is suitable for current use for risk assessment in individuals from the United Kingdom.

Cardiovascular mortality risk beyond 10 years in men and women; long-term follow-up from the EPIC-Norfolk prospective population study

Abstract Introduction Current primary prevention strategies in cardiovascular (CV) disease focus on initiating preventive interventions in people at high 10-year risk of CV mortality. However, initiating such strategies should be beneficial not only in the first 10 years, but throughout life. Established risk algorithms estimate the risk of 10-year CV mortality, but limited evidence is available about the relationship between 10-year and longer-term CV mortality. Purpose To compare cumulative incidence of CV mortality in a population cohort at 10- and 20-years follow-up, stratified by sex. Methods We analysed CV mortality at 10-years and 20-years follow-up using Kaplan-Meier estimates among men and women aged 39–70 years without baseline CV disease or diabetes mellitus in the large, prospective population-based EPIC-Norfolk cohort. CV mortality included death with as underlying or contributing cause ischaemic heart disease, heart failure, cerebrovascular disease or peripheral artery disease. Results We analysed data from 20,453 participants (56% women), with a mean age of 56±8 years, and median (IQR) follow-up of 22 (21–23) years. At baseline, there were no clinically relevant differences in CV risk factors between men and women. Overall cumulative CV mortality rate was 1.9% (384 deaths) in the first 10 years, and 7.3% (995 deaths) at 20 years follow-up (ratio 3.8). Among men, 10-year CV mortality was 2.9% (249 deaths), and 9.6% (785 deaths) at 20 years follow-up (ratio 3.3). Among women, CV mortality was 1.2% (135 deaths) at 10 year and 5.5% (594 deaths) at 20 years follow-up (ratio 4.6). Conclusion We observed an incremental increase in CV mortality beyond the 10-year scope of current established CV risk algorithms. At 20 years follow-up, CV mortality rates were 3–5 times higher compared with the first decade, indicating that 20-year CV mortality risk for both men and women cannot simply be estimated based on extrapolation of 10-year risk. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): EPIC-Norfolk is supported by programme grants from the Medical Research Council UK (MRC G0401527, MRC G0701863, MRC G1000143) and Cancer Research UK (CRUK 8257).

Impact of cholesterol on proinflammatory monocyte production by the bone marrow.

AimPreclinical work indicates that low-density lipoprotein cholesterol (LDL-C) not only drives atherosclerosis by directing the innate immune response at plaque level but also augments proinflammatory monocyte production in the bone marrow (BM) compartment. In this study, we aim to unravel the impact of LDL-C on monocyte production in the BM compartment in human subjects.Methods and resultsA multivariable linear regression analysis in 12 304 individuals of the EPIC-Norfolk prospective population study showed that LDL-C is associated with monocyte percentage (β = 0.131 [95% CI: 0.036–0.225]; P = 0.007), at the expense of granulocytes (β = −0.876 [95% CI: −1.046 to −0.705]; P < 0.001). Next, we investigated whether altered haematopoiesis could explain this monocytic skewing by characterizing CD34+ BM haematopoietic stem and progenitor cells (HSPCs) of patients with familial hypercholesterolaemia (FH) and healthy normocholesterolaemic controls. The HSPC transcriptomic profile of untreated FH patients showed increased gene expression in pathways involved in HSPC migration and, in agreement with our epidemiological findings, myelomonocytic skewing. Twelve weeks of cholesterol-lowering treatment reverted the myelomonocytic skewing, but transcriptomic enrichment of monocyte-associated inflammatory and migratory pathways persisted in HSPCs post-treatment. Lastly, we link hypercholesterolaemia to perturbed lipid homeostasis in HSPCs, characterized by lipid droplet formation and transcriptomic changes compatible with increased intracellular cholesterol availability.ConclusionsCollectively, these data highlight that LDL-C impacts haematopoiesis, promoting both the number and the proinflammatory activation of circulating monocytes. Furthermore, this study reveals a potential contributory role of HSPC transcriptomic reprogramming to residual inflammatory risk in FH patients despite cholesterol-lowering therapy.

Plasma trimethylamine N-oxide (TMAO) levels predict future risk of coronary artery disease in apparently healthy individuals in the EPIC-Norfolk prospective population study

BackgroundRecent studies show a mechanistic link between gut microbiota-dependent formation of the atherosclerosis- and thrombosis-promoting metabolite trimethylamine N-oxide (TMAO) and cardiovascular disease (CVD). The clinical utility of TMAO in apparently healthy subjects for predicting incident CVD risks is unclear. Methods and ResultsIn the EPIC-Norfolk community-based study, we examined baseline fasting levels of TMAO and two of its nutrient precursors, choline and betaine, in a case:control design study comparing apparently European healthy middle-aged participants who subsequently develop CVD (Cases, n = 908) vs those who did not (Controls, n = 1,273) over an ensuing average follow-up period of 8 years. In participants who developed CVD vs controls, higher plasma TMAO (3.70 [IQR 2.50-6.41]μM vs 3.25 [IQR 2.19-52,1.15]μM; P < .001) and choline levels (9.09 [IQR 7.87-10.53]μM vs 8.89 [IQR 7.66-10.13]μM; P = .001) were observed. Following adjustments for traditional risk factors, elevated TMAO (adjusted odds ratio (OR) 1.58 [95% confidence interval (CI) 1.21-2.06], P < .001) and choline levels (adjusted OR 1.31 [95%CI 1.00-1.72], P < .05) remained predictive of incident CVD development. The clinical prognostic utility of TMAO remained significant and essentially unchanged regardless of the level of cutoff chosen between 1.5 uM (10%ile) to 10.5 uM (90%ile). ConclusionIn apparently healthy participants of the community-based middle-aged EPIC-Norfolk population, elevated plasma levels of the gut microbe-dependent metabolite TMAO, and its nutrient precursor choline, predict incident risk for CVD development independent of traditional risk factors.

FRIED FOOD AND POSSIBLE HEALTH HAZARDS

FRIED FOOD AND POSSIBLE HEALTH HAZARDS

Relationship of lipoprotein-associated apolipoprotein C-III with lipid variables and coronary artery disease risk: The EPIC-Norfolk prospective population study

Plasma apolipoprotein C-III (apoC-III) levels are associated with coronary artery disease (CAD) risk. To assess whether lipoprotein-associated apoC-III levels predict risk of CAD events. apoC-III associated with apoB, apoAI, and Lp(a) (apoCIII-apoB, apoCIII-apoAI, and apoCIII-Lp(a), respectively) were measured using high-throughput chemiluminescent enzyme-linked immunoassays in 2711 subjects (1879 controls and 832 cases with CAD) in the European Prospective Investigation into Cancer and Nutrition-Norfolk prospective population study with 7.4years of follow-up. These measures were correlated with a variety of lipid measurements and the presence of CAD. The indices of "total apoCIII-apoB" and "total apoCIII-apoAI" were derived by multiplying plasma apoB and apoAI, respectively. apoCIII-apoB (P=.001), apoCIII-Lp(a) (P<.001), apoCIII-apoAI (P=.005) were higher in cases vs controls; tended to correlate positively with body mass index, hsCRP, apoC-III, low-density lipoprotein (LDL) cholesterol, triglycerides, remnant cholesterol, very low density lipoprotein, LDL and high-density lipoprotein particle number and very low density lipoprotein size; but negatively with LDL and high-density lipoprotein particle size (P<.001 for all). apoCIII-apoB, apoCIII-apoAI, apoCIII-Lp(a), total apoCIII-Lp(a), and total apoCIII-apoB were predictors of CAD after adjustment of age, sex, body mass index, smoking, diabetes, hypertensive and lipid-lowering drug use, but they lost their significance after further adjustment of lipid and lipoprotein variables. This study suggests that enzyme-linked immunoassay-measured lipoprotein-associated apoC-III markers reflect atherogenic lipid particles but do not independently predict risk of CAD events.

P5802Individual and combined impact of modifiable lifestyle factors on atrial fibrillation in apparently healthy men and women: the epic-norfolk prospective population study

P5802Individual and combined impact of modifiable lifestyle factors on atrial fibrillation in apparently healthy men and women: the epic-norfolk prospective population study

Alcohol consumption and future hospital usage: The EPIC-Norfolk prospective population study.

BackgroundHeavy drinkers of alcohol are reported to use hospitals more than non-drinkers, but it is unclear whether light-to-moderate drinkers use hospitals more than non-drinkers.ObjectiveWe examined the relationship between alcohol consumption in 10,883 men and 12,857 women aged 40–79 years in the general population and subsequent admissions to hospital and time spent in hospital.MethodsParticipants from the EPIC-Norfolk prospective population-based study were followed for ten years (1999–2009) using record linkage.ResultsCompared to current non-drinkers, men who reported any alcohol drinking had a lower risk of spending more than twenty days in hospital multivariable adjusted OR 0.80 (95%CI 0.68–0.94) after adjusting for age, smoking status, education, social class, body mass index and prevalent diseases. Women who were current drinkers were less likely to have any hospital admissions multivariable adjusted OR 0.84 (95%CI 0.74–0.95), seven or more admissions OR 0.77 (95% CI 0.66–0.88) or more than twenty hospital days OR 0.70 (95%CI 0.62–0.80). However, compared to lifelong abstainers, men who were former drinkers had higher risk of any hospital admissions multivariable adjusted OR 2.22 (95%CI 1.51–3.28) and women former drinkers had higher risk of seven or more admissions OR 1.30 (95%CI 1.01–1.67).ConclusionCurrent alcohol consumption was associated with lower risk of future hospital usage compared with non-drinkers in this middle aged and older population. In men, this association may in part be due to whether former drinkers are included in the non-drinker reference group but in women, the association was consistent irrespective of the choice of reference group. In addition, there were few participants in this cohort with very high current alcohol intake. The measurement of past drinking, the separation of non-drinkers into former drinkers and lifelong abstainers and the choice of reference group are all influential in interpreting the risk of alcohol consumption on future hospitalisation.

Cardiovascular disease risk associated with elevated lipoprotein(a) attenuates at low low-density lipoprotein cholesterol levels in a primary prevention setting.

Lipoprotein(a) (Lp(a)) elevation is a causal risk factor for cardiovascular disease (CVD). It has however been suggested that elevated Lp(a) causes CVD mainly in individuals with high low-density lipoprotein cholesterol (LDL-C) levels. We hypothesized that the risk associated with high Lp(a) levels would largely be attenuated at low LDL-C levels. In 16654 individuals from the EPIC-Norfolk prospective population study, and in 9448 individuals from the Copenhagen City Heart Study (CCHS) parallel statistical analyses were performed. Individuals were categorized according to their Lp(a) and LDL-C levels. Cut-offs were set at the 80th cohort percentile for Lp(a). Low-density lipoprotein cholesterol cut-offs were set at 2.5, 3.5, 4.5, and 5.5 mmol/L. Low-density lipoprotein cholesterol levels in the primary analyses were corrected for Lp(a)-derived LDL-C (LDL-Ccorr). Multivariable-adjusted hazard ratios were calculated for each category. The category with LDL-Ccorr <2.5 mmol/L and Lp(a) <80th cohort percentile was used as reference category. In the EPIC-Norfolk and CCHS cohorts, individuals with an Lp(a) ≥80th percentile were at increased CVD risk compared with those with Lp(a) <80th percentile for any LDL-Ccorr levels ≥2.5 mmol/L. In contrast, for LDL-Ccorr <2.5 mmol/L, the risk associated with elevated Lp(a) attenuated. However, there was no interaction between LDL-Ccorr and Lp(a) levels on CVD risk in either cohort. Lipoprotein(a) and LDL-C are independently associated with CVD risk. At LDL-C levels below <2.5 mmol/L, the risk associated with elevated Lp(a) attenuates in a primary prevention setting.

Individual and combined impact of lifestyle factors on atrial fibrillation in apparently healthy men and women: The EPIC-Norfolk prospective population study.

Background Lifestyle factors are important targets for prevention. The cumulative impact of healthy lifestyle on atrial fibrillation in the population has not been quantified. Design Prospective population-based cohort study. Methods Four lifestyle factors (normal weight, currently not smoking, no or moderate alcohol intake, and physically not inactive) were assessed in apparently healthy 21,499 men and women aged 39-79 years participating in the EPIC study in Norfolk, UK. The age and sex-adjusted hazard (95% confidence interval) of hospital admission with a diagnosis of atrial fibrillation during an average follow-up of 17.1 years was examined for each factor separately and for a health score comprising factors with significant impact. Results Normal weight, currently not smoking and low alcohol intake were associated with a significantly lower risk of atrial fibrillation, whereas not being physically inactive showed no significant association. We used a score of one point each for not smoking, low alcohol intake and body mass index 25 to 27.5 kg/m2, and two points for body mass index < 25 kg/m2. Compared with men and women with four health points, hazard ratios of atrial fibrillation were 1.25 (1.11-1.41), 1.56 (1.39-1.75), 1.83 (1.56-2.16) and 2.82 (1.85-4.29) for participants with three, two, one and no health points, respectively ( p < 0.0001 for trend). Results were consistent by sex, age, education level, social class and after excluding participants with hypertension and diabetes. Conclusion Three lifestyle factors combined predict an almost 2.8-fold difference in the risk of atrial fibrillation in men and women.

Lipoprotein(a) improves cardiovascular risk prediction based on the ACC/AHA and score algorithms in intermediate risk patients; the EPIC-Norfolk prospective population study

Aim: To determine if lipoprotein(a) [Lp(a)] improves risk classification based on the American College of Cardiology and American Heart Association (ACC/AHA) Pooled Cohort Equations and Systematic Coronary Risk Evaluation (SCORE) risk algorithms.

Ideal cardiovascular health influences cardiovascular disease risk associated with high lipoprotein(a) levels and genotype: The EPIC-Norfolk prospective population study

Background and aimsLipoprotein(a) (Lp[a]) is a strong genetic risk factor for cardiovascular disease (CVD). The American Heart Association has prioritised seven cardiovascular health metrics to reduce the burden of CVD: body mass index, healthy diet, physical activity, smoking status, blood pressure, diabetes and cholesterol levels (together also known as ideal cardiovascular health). Our objective was to determine if individuals with high Lp(a) levels could derive cardiovascular benefits if characterized by ideal cardiovascular health. MethodsA total of 14,051 participants of the EPIC-Norfolk study were stratified according to the cardiovascular health score (based on the number of health metrics with an ideal, intermediate or poor status). Of them, 1732 had a CVD event during a mean follow-up of 11.5 years. Cox proportional hazards models were used to describe the association between the cardiovascular health score and Lp(a) level or genotype (as estimated by the rs10455872 variant) with the risk of CVD. ResultsWe observed little or no differences in serum Lp(a) levels across the seven cardiovascular health metric categories. Among participants with high serum Lp(a) levels ≥50 mg/dl), those in the highest (i.e. healthiest) cardiovascular health score category (10–14) had an adjusted hazard ratio for cardiovascular disease of 0.33 (95% CI = 0.17–0.63, p = 0.001) compared to participants in the lowest (i.e. unhealthiest) cardiovascular health score category(0–4). Similar results were obtained when we replaced Lp(a) with rs10455872. ConclusionsAlthough Lp(a) levels are only slightly influenced by cardiovascular health metrics, an ideal cardiovascular health could substantially reduce CVD risk associated with high Lp(a) levels or genotype.

Plasma apolipoprotein CIII levels and incident coronary artery disease risk: The EPIC-Norfolk prospective population study

Plasma apolipoprotein CIII levels and incident coronary artery disease risk: The EPIC-Norfolk prospective population study

Population and assay thresholds for the predictive value of lipoprotein(a) for risk of coronary artery disease: The EPIC-Norfolk prospective population study

Population and assay thresholds for the predictive value of lipoprotein(a) for risk of coronary artery disease: The EPIC-Norfolk prospective population study

Population and assay thresholds for the predictive value of lipoprotein (a) for coronary artery disease: the EPIC-Norfolk Prospective Population Study

Variable agreement exists between different lipoprotein (a) [Lp(a)] measurement methods, but their clinical relevance remains unclear. The predictive value of Lp(a) measured by two different assays [Randox and University of California, San Diego (UCSD)] was determined in 623 coronary artery disease (CAD) cases and 948 controls in a case-control study within the EPIC-Norfolk Prospective Population Study. Participants were divided into sex-specific quintiles, and by Lp(a) <50 versus ∼50 mg/dl, which represents the 80th percentile in northern European subjects. Randox and UCSD Lp(a) levels were strongly correlated; Spearman's correlation coefficients for men, women, and sexes combined were 0.905, 0.915, and 0.909, respectively (P< 0.001 for each). The >80th percentile cutoff values, however, were 36 mg/dl and 24 mg/dl for the Randox and UCSD assays, respectively. Despite this, Lp(a) levels were significantly associated with CAD risk, with odds ratios of 2.18 (1.58-3.01) and 2.35 (1.70-3.26) for people in the top versus bottom Lp(a) quintile for the Randox and UCSD assays, respectively. This study demonstrates that CAD risk is present at lower Lp(a) levels than the currently suggested optimal Lp(a) level of <50 mg/dl. Appropriate thresholds may need to be population and assay specific until Lp(a) assays are standardized and Lp(a) thresholds are evaluated broadly across all populations at risk for CVD and aortic stenosis.

Heterogeneous impact of classic atherosclerotic risk factors on different arterial territories: the EPIC-Norfolk prospective population study.

Particular atherosclerotic risk factors may differ in their association with atherosclerosis across vascular territories. Few studies have compared the associations between multiple risk factors and cardiovascular disease (CVD) manifestations in one population. We studied the strength of the associations between traditional risk factors including coronary artery disease (CAD), ischaemic and haemorrhagic stroke, abdominal aortic aneurysms (AAAs), and peripheral arterial disease (PAD). This analysis included 21 798 participants of the EPIC-Norfolk population study, without previous CVD. Events were defined as hospitalization or mortality, coded using ICD-10. The associations between the risk factors, such as low-density lipoprotein cholesterol, systolic blood pressure (SBP), and smoking, and the various CVD manifestations were compared using competing risk analyses. During 12.1 years, 3087 CVD events were recorded. The associations significantly differed across CVD manifestations. Low-density lipoprotein cholesterol was strongly associated with CAD [adjusted hazard rate (aHR) highest vs. lowest quartile 1.63, 95% CI 1.44-1.86]. Systolic blood pressure was a strong risk factor for PAD (aHR highest vs. lowest quartile 2.95, 95% CI 1.78-4.89) and ischaemic stroke (aHR highest vs. lowest quartile 2.48, 95% CI 1.55-3.97), but not for AAA. Smoking was strongly associated with incident AAA (aHR current vs. never 7.66, 95% CI 4.50-13.04) and PAD (aHR current vs. never 4.66, 95% CI 3.29-6.61), but not with haemorrhagic stroke. The heterogeneity in the risk factor-CVD associations supports the concept of pathophysiological differences between atherosclerotic CVD manifestations and could have implications for CVD prevention.

Ideal cardiovascular health and risk of cardiovascular events in the EPIC-Norfolk prospective population study.

The American Heart Association has prioritised seven cardiovascular health metrics to reduce the cardiovascular burden, including: body mass index, healthy diet, physical activity, smoking status, blood pressure, glycated haemoglobin A1c and total cholesterol. The aim of the current study was to assess the association between the American Heart Association-defined health metrics and the risk of cardiovascular events in the EPIC-Norfolk prospective study. Prospective cohort study. An overall cardiovascular health score was calculated based on the number of health metrics including ideal, intermediate or poor. Cox proportional hazards models were used to describe the association of the seven metrics separately and the overall health score with risk of coronary heart disease, stroke and cardiovascular disease. A total of 10,043 participants was included in the analysis (follow-up 1993-2008). For all individual health metrics a more ideal status was associated with a lower risk of cardiovascular events. As for the overall cardiovascular health score, those in the highest (i.e. healthiest) category (score 12-14) had an adjusted hazard ratio for coronary heart disease of 0.07 (95% confidence interval (CI) 0.02-0.29, P < 0.001), for stroke of 0.16 (95% CI 0.02-1.37, P = 0.09) and for cardiovascular disease of 0.07 (95% CI 0.02-0.23, P < 0.001), compared to people in the lowest (i.e. unhealthiest) category (score 0-2). The overall cardiovascular health score was strongly and inversely associated with risk of coronary heart disease, stroke and cardiovascular disease. Our data suggest that even small improvements in modifiable risk factors may lead to substantial reductions in the risks of cardiovascular events.

Total anticholinergic burden and risk of mortality and cardiovascular disease over 10 years in 21,636 middle-aged and older men and women of EPIC-Norfolk prospective population study.

Studies have raised concerns that medications with anticholinergic property have potential adverse effects on health outcomes. The objective of this study is to examine the prospective relationships between total anticholinergic burden (ACB) from medications and mortality, and cardiovascular disease (CVD) in a general population. Observational study. Community cohort. We examined data collected from 21,636 men and women without cancer at the baseline who participated in a baseline survey 1993-97 in the European Prospective Investigation into Cancer (EPIC)-Norfolk. They were followed until 2009/11. We performed Cox-proportional hazards models to determine the associations between total ACB and the subsequent risk of all-cause mortality and incident CVD during the follow-up. There were a total of 4,342 people died and 7,328 had an incident CVD during the study follow-up (total person years=322,321 years for mortality and 244,119 years for CVD event). Compared with people with no anticholinergic burden (ACB=0), people with total ACB≥3 from medications had hazards ratios of 1.83 (1.53, 2.20) and 2.17 (1.87, 2.52) for mortality and CVD incidence outcomes, respectively, after adjusting for potential confounders. Repeating the analyses after excluding people with prevalent illnesses, and events occurring within the first 2 years of follow-up, only slightly attenuated the results. There appear to be a class effect as well as dose-response relationship between the ACB and both outcomes. Future research should focus on understanding the relationship between ACB and mortality, and cardiovascular disease and possibly minimising ACB load where feasible.