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Importance: It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE)., Objective: To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism., Design, Setting, and Participants: This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731 728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421 537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018., Exposures: A panel of several established cardiovascular risk factors., Main Outcomes and Measures: Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CHD], 25 131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI)., Results: Of the 731 728 participants from the ERFC, 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421 537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers., Conclusions and Relevance: Older age, smoking, and adiposity were consistently associated with higher VTE risk.

Background/objectives: We studied the ecologic relationships of food groups, macronutrients, eating patterns, and an a priori food pattern score (Mediterranean Adequacy Index: MAI) with long-term CHD mortality rates in the Seven Countries Study., Subjects/methods: Sixteen cohorts (12,763 men aged 40-59 years) were enrolled in the 1960s in seven countries (US, Finland, The Netherlands, Italy, Greece, former Yugoslavia: Croatia/Serbia, Japan). Dietary surveys were carried out at baseline and only in a subsample of each cohort. The average food consumption of each cohort was chemically analyzed for individual fatty acids and carbohydrates., Results: Ecologic correlations of diet were computed across cohorts for 50-year CHD mortality rates; 97% of men had died in cohorts with 50-year follow-up. CHD death rates ranged 6.7-fold among cohorts. At baseline, hard fat was greatest in northern Europe, olive oil in Greece, meat in the US, sweet products in northern Europe and the US, and fish in Japan. The MAI was high in Mediterranean and Japanese cohorts. The 50-year CHD mortality rates of the cohorts were closely positively ecologically correlated (r = 0.68-0.92) with average consumption of hard fat, sweet products, animal foods, saturated fat, and sucrose, but not with naturally occurring sugars. Vegetable foods, starch, and the a priori pattern MAI were inversely correlated (r = -0.59 to -0.91) with CHD mortality rates., Conclusions: Long-term CHD mortality rates had statistically significant ecologic correlations with several aspects of diet consumed in the 1960s, the traditional Mediterranean and Japanese patterns being rich in vegetable foods, and low in sweet products and animal foods.

Objectives: To compare the magnitude of multivariable coefficients and hazard ratios of four cardiovascular risk factors across five worldwide regions of the Seven Countries Study in predicting 50-year coronary deaths., Material and Methods: A total of 13 cohorts of middle-aged men at entry (40-59 years old) were enrolled in the mid-1900s from five relatively homogeneous groups of cohorts (areas): USA, Finland and Zutphen - the Netherlands, Italy and Greece, Serbia, Japan for a total of 10,368 middle-aged men. The major risk factors measured at baseline were age, number of cigarettes smoked, systolic blood pressure and serum cholesterol. Cox proportional hazards models were solved for 50-year (45 years for Serbia) deaths from coronary heart disease (CHD), and the multivariable coefficients were compared for heterogeneity., Results: The highest levels of risk factors and CHD death rates were found in Finland and Zutphen - the Netherlands and the lowest in Japan. All four risk factors were predictive for long-term CHD mortality in all regions, except serum cholesterol in Japan where the mean levels and CHD events were lowest. Tests of heterogeneity of coefficients for single risk factors in predicting CHD mortality were non-significant across the five areas. The same analyses for the first 25 years of follow-up produced similar findings., Conclusions: The strength of the multivariable associations of four major traditional CHD risk factors with long-term CHD mortality appears to be relatively homogeneous across areas, pending needed further evidence.

We aimed at performing a calibration and re-calibration process using six standard risk factors from Northern (NE, N = 2360) or Southern European (SE, N = 2789) middle-aged men of the Seven Countries Study, whose parameters and data were fully known, to establish whether re-calibration gave the right answer. Greenwood-Nam-D'Agostino technique as modified by Demler (GNDD) in 2015 produced chi-squared statistics using 10 deciles of observed/expected CHD mortality risk, corresponding to Hosmer-Lemeshaw chi-squared employed for multiple logistic equations whereby binary data are used. Instead of the number of events, the GNDD test uses survival probabilities of observed and predicted events. The exercise applied, in five different ways, the parameters of the NE-predictive model to SE (and vice-versa) and compared the outcome of the simulated re-calibration with the real data. Good re-calibration could be obtained only when risk factor coefficients were substituted, being similar in magnitude and not significantly different between NE-SE. In all other ways, a good re-calibration could not be obtained. This is enough to praise for an overall need of re-evaluation of most investigations that, without GNDD or another proper technique for statistically assessing the potential differences, concluded that re-calibration is a fair method and might therefore be used, with no specific caution.

Objectives: This analysis deals with the ecologic relationships of dietary fatty acids, food groups and the Mediterranean Adequacy Index (MAI, derived from 15 food groups) with 50-year all-cause mortality rates in 16 cohorts of the Seven Countries Study., Material and Methods: A dietary survey was conducted at baseline in cohorts subsamples including chemical analysis of food samples representing average consumptions. Ecologic correlations of dietary variables were computed across cohorts with 50-year all-cause mortality rates, where 97% of men had died., Results: There was a 12-year average age at death population difference between extreme cohorts. In the 1960s the average population intake of saturated (S) and trans (T) fatty acids and hard fats was high in the northern European cohorts while monounsaturated (M), polyunsaturated (P) fatty acids and vegetable oils were high in the Mediterranean areas and total fat was low in Japan. The 50-year all-cause mortality rates correlated (r= -0.51 to -0.64) ecologically inversely with the ratios M/S, (M + P)/(S + T) and vegetable foods and the ratio hard fats/vegetable oils. Adjustment for high socio-economic status strengthened (r= -0.62 to -0.77) these associations including MAI diet score., Conclusion: The protective fatty acids and vegetable oils are indicators of the low risk traditional Mediterranean style diets. KEY MESSAGES We aimed at studying the ecologic relationships of dietary fatty acids, food groups and the Mediterranean Adequacy Index (MAI, derived from 15 food groups) with 50-year all-cause mortality rates in the Seven Countries Study. The 50-year all-cause mortality rates correlated (r = -0.51 to -0.64) ecologically inversely with the ratios M/S [monounsaturated (M) + polyunsaturated (P)]/[saturated (S) + trans (T)] fatty acids and vegetable foods and the ratio hard fats/vegetable oils. After adjustment for high socio-economic status, associations with the ratios strengthened (r = -0.62 to -0.77) including also the MAI diet score. The protective fatty acids and vegetable oils are indicators of the low risk traditional Mediterranean style diets.

Objectives: The relationships were explored of some cardiovascular risk factors to typical (TYP) and atypical (ATYP) fatal coronary events (CHD)., Material and Methods: Thirteen cohorts of 40-59 year-old men of the Seven Countries Study were followed-up for 40 years (N = 9704 heart disease free subjects). Fatal TYP-CHD were classified when manifested as myocardial infarction, other acute coronary syndromes, angina pectoris and sudden death; and as ATYP-CHD when manifested only as heart failure or arrhythmia in the absence of other clear etiologies. Death rates were computed for single countries separately for TYP and ATYP and for different lengths of follow-up. Cox models included: age, smoking habits, systolic blood pressure (SBP), serum cholesterol (CHOL), forced expiratory volume in ¾ sec (FEV) and diabetes., Results: TYP-CHD was more common in North American and Northern European countries, while ATYP-CHD were more common in Southern and Eastern Europe. Age at death was 5 years greater for ATYP-CHD than for TYP-CHD. Cox models in the pool of 13 cohorts showed that coefficient for age was significantly larger for ATYP-CHD (hazard ratio, HR: 2.36; confidence intervals CI: 2.18 - 2.26) versus TYP-CHD (HR 1.50, CI 1.43-1.58) while coefficients for CHOL was larger and significant for TYP-CHD (HR 1.29, CI 1.22-1.35) but not for ATYP-CHD (HR 0.93, CI 0.85-1.03). SBP, smoking habits, FEV and diabetes all predicted both conditions almost equally., Conclusion: The different relationships of CHOL and age with the two types of fatal CHD suggest that the two groups of manifestations may belong to different diseases., (© 2013.)

Background: Dietary polyunsaturated fatty acids (PUFA) are inversely related to coronary heart disease (CHD) in epidemiological studies. We examined the associations of plasma n-6 and n-3 PUFA in cholesteryl esters with fatal CHD in a nested case-control study. Additionally, we performed a dose-response meta-analysis of similar prospective studies on cholesteryl ester PUFA., Methods: We used data from two population-based cohort studies in Dutch adults aged 20-65 y. Blood and data collection took place from 1987-1997 and subjects were followed for 8-19 y. We identified 279 incident cases of fatal CHD and randomly selected 279 controls, matched on age, gender, and enrollment date. Odds ratios (OR) were calculated per standard deviation (SD) increase of cholesteryl ester PUFA., Results: After adjustment for confounders, the OR (95%CI) for fatal CHD per SD increase in plasma linoleic acid was 0.89 (0.74-1.06). Additional adjustment for plasma total cholesterol and systolic blood pressure attenuated this association (OR:0.95; 95%CI: 0.78-1.15). Arachidonic acid was not associated with fatal CHD (OR per SD:1.11; 95%CI: 0.92-1.35). The ORs (95%CI) for fatal CHD for an SD increase in n-3 PUFA were 0.92 (0.74-1.15) for alpha-linolenic acid and 1.06 (0.88-1.27) for EPA-DHA. In the meta-analysis, a 5% higher linoleic acid level was associated with a 9% lower risk (relative risk: 0.91; 95% CI: 0.84-0.98) of CHD. The other fatty acids were not associated with CHD., Conclusion: In this Dutch population, n-6 and n-3 PUFA in cholesteryl esters were not significantly related to fatal CHD. Our data, together with findings from previous prospective studies, support that linoleic acid in plasma cholesteryl is inversely associated with CHD.

Objective: Consuming a variety of fruit and vegetables provides many different micronutrients and bioactive compounds. Whether this contributes to the beneficial association between fruit and vegetables and incident CHD and stroke is unknown., Design: Prospective population-based cohort study., Setting: The Netherlands., Subjects: Men and women (n 20 069) aged 20-65 years. Participants completed a validated 178-item FFQ, including nine fruit and thirteen vegetable items. Variety in fruit and vegetables was defined as the sum of different items consumed at least once per 2 weeks over the previous year. Hazard ratios (HR) for variety in relation to incident CHD and stroke were calculated using multivariable Cox proportional hazards models additionally adjusted for quantity of fruit and vegetables., Results: Variety and quantity in fruit and vegetables were highly correlated (r = 0.81). Variety was not associated with total energy intake (r = -0.01) and positively associated with nutrient intakes, particularly vitamin C (r = 0.70). During 10 years of follow-up, 245 cases of CHD and 233 cases of stroke occurred. Variety in vegetables (HR per 2 items = 1.05; 95 % CI 0.94, 1.17) and in fruit (HR per 2 items = 1.00; 95 % CI 0.87, 1.15) were not related to incident CHD. Variety in vegetables (HR per 2 items = 0.93; 95 % CI 0.83, 1.04) and in fruit (HR per 2 items = 1.03; 95 % CI 0.89, 1.18) were also not related to incident stroke., Conclusions: More variety in fruit and vegetable consumption was associated with higher intakes of fruit and vegetables and micronutrients. Independently of quantity, variety in fruit and vegetables was related neither to incident CHD nor to incident stroke.

We studied the associations of a difference in linoleic acid or carbohydrate intake with plasma cholesterol levels and risk of CHD in a prospective cohort study in the Netherlands. Data on diet (FFQ) and plasma total and HDL-cholesterol were available at baseline (1993-7) of 20,069 men and women, aged 20-65 years, who were initially free of CVD. Incidence of CHD was assessed through linkage with mortality and morbidity registers. During an average of 10 years of follow-up, 280 CHD events occurred. The intake of linoleic acid ranged from 3·6 to 8·0 % of energy (en%), whereas carbohydrate intake ranged from 47·6 to 42·5 en% across quintiles of linoleic acid intake. Linoleic acid intake was inversely associated with total cholesterol and HDL-cholesterol in women but not in men. Linoleic acid intake was not associated with the ratio of total to HDL-cholesterol. No association was observed between linoleic acid intake and CHD incidence, with hazard ratios varying between 0·83 and 1·00 (all P>0·05) compared to the bottom quintile. We conclude that a 4-5 en% difference in linoleic acid or carbohydrate intake did not translate into either a different ratio of total to HDL-cholesterol or a different CHD incidence.

The colours of the edible part of fruit and vegetables indicate the presence of specific micronutrients and phytochemicals. The extent to which fruit and vegetable colour groups contribute to CHD protection is unknown. We therefore examined the associations between fruit and vegetables of different colours and their subgroups and 10-year CHD incidence. We used data from a prospective population-based cohort including 20 069 men and women aged 20-65 years who were enrolled between 1993 and 1997. Participants were free of CVD at baseline and completed a validated 178-item FFQ. Hazard ratios (HR) for the association between green, orange/yellow, red/purple, white fruit and vegetables and their subgroups with CHD were calculated using multivariable Cox proportional hazards models. During 10 years of follow-up, 245 incident cases of CHD were documented. For each 25 g/d increase in the intake of the sum of all four colours of fruit and vegetables, a borderline significant association with incident CHD was found (HR 0·98; 95 % CI 0·97, 1·01). No clear associations were found for the colour groups separately. However, each 25 g/d increase in the intake of deep orange fruit and vegetables was inversely associated with CHD (HR 0·74; 95 % CI 0·55, 1·00). Carrots, their largest contributor (60 %), were associated with a 32 % lower risk of CHD (HR 0·68; 95 % CI 0·48, 0·98). In conclusion, though no clear associations were found for the four colour groups with CHD, a higher intake of deep orange fruit and vegetables and especially carrots may protect against CHD.

A recent meta-analysis of prospective cohort studies has not found an association between dietary saturated fat intake and CHD incidence. This funnelled the discussion about the importance of the recommendation to lower the intake of saturated fat for the prevention of CHD. At the same time a document of the European Food Safety Authority has suggested that specific quantitative recommendations are not needed for individual fatty acids but that more general statements can suffice. In this review, we discuss methodological aspects of the absence of association between SFA intake and CHD incidence in prospective cohort studies. We also summarise the results of the controlled dietary experiments on blood lipids and on CHD incidence in which saturated fat was replaced by either cis-unsaturated fat or carbohydrates. Finally, we propose a nutritionally adequate diet with an optimal fatty acid composition for the prevention of CHD in the context of dietary patterns. Such diets are characterised by a low intake of saturated fat, and as low as possible intake of trans-fat and fulfil the requirements for the intake of n-6 and n-3 fatty acids. No recommendation is needed for the intake of cis-MUFA.

Background: Whether intake of alpha-linolenic acid (ALA), the plant-derived n-3 polyunsaturated fatty acid (PUFA), could prevent cardiovascular diseases is not yet clear. We examined the associations of ALA intake with 10-year incidence of coronary heart disease (CHD) and stroke in the Netherlands., Methods: Data were collected from a general population of 20,069 generally healthy men and women, aged 20 to 65 years. Habitual diet was assessed at baseline (1993-1997) with a validated 178-item food frequency questionnaire. Incidences of CHD and stroke were assessed through linkage with mortality and morbidity registers. Hazard ratios (HR) were calculated with multivariable Cox proportional hazards models, adjusted for age, gender, lifestyle, and dietary factors., Results: During 8-13 years of follow-up, we observed 280 incident CHD events (19% fatal) and 221 strokes (4% fatal). Intakes of energy-adjusted ALA in quintiles ranged from less than 1.0 g/d in the bottom quintile (Q1) to more than 1.9 g/d in the top quintile (Q5). ALA intake was not associated with incident CHD, with HRs varying between 0.89 and 1.01 (all p>0.05) in Q2-Q5 compared with the bottom quintile of ALA intake. For incident stroke, however, participants in Q2-Q5 had a 35-50% lower risk compared with the reference group. HRs were 0.65 (0.43-0.97), 0.49 (0.31-0.76), 0.53 (0.34-0.83), and 0.65 (0.41-1.04) for Q2-Q5 respectively., Conclusion: In this general Dutch population, ALA intake was not associated with incident CHD. The data suggested that a low intake of ALA may be a risk factor for incident stroke. These results warrant confirmation in other population-based studies and in trials.

Background: Prospective cohort studies have shown that high fruit and vegetable consumption is inversely associated with coronary heart disease (CHD). Whether food processing affects this association is unknown. Therefore, we quantified the association of fruit and vegetable consumption with 10-year CHD incidence in a population-based study in the Netherlands and the effect of processing on these associations., Methods: Prospective population-based cohort study, including 20,069 men and women aged 20 to 65 years, enrolled between 1993 and 1997 and free of cardiovascular disease at baseline. Diet was assessed using a validated 178-item food frequency questionnaire. Hazard ratios (HR) were calculated for CHD incidence using multivariable Cox proportional hazards models., Results: During a mean follow-up time of 10.5y, 245 incident cases of CHD were documented, which comprised 211 non-fatal acute myocardial infarctions and 34 fatal CHD events. The risk of CHD incidence was 34% lower for participants with a high intake of total fruit and vegetables (>475 g/d; HR: 0.66; 95% CI: 0.45-0.99) compared to participants with a low total fruit and vegetable consumption (≤241 g/d). Intake of raw fruit and vegetables (>262 g/d vs ≤92 g/d; HR: 0.70; 95% CI: 0.47-1.04) as well as processed fruit and vegetables (>234 g/d vs ≤113 g/d; HR: 0.79; 95% CI: 0.54-1.16) were inversely related with CHD incidence., Conclusion: Higher consumption of fruit and vegetables, whether consumed raw or processed, may protect against CHD incidence.

We assessed the dose-response relations within a low range of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and fish intake on fatal coronary heart disease (CHD) and nonfatal myocardial infarction (MI). In a Dutch population-based cohort study, EPA+DHA and fish intake were assessed at baseline among 21,342 participants aged 20-65 y with no history of MI or stroke. Hazard ratios were calculated with Cox proportional-hazard models. During 9-14 y of follow-up (mean 11.3 y), 647 participants (3%) died, of which 82 of CHD. Fatal CHD mainly comprised MI (64 cases). In total, 252 participants survived an MI. Median intakes in quartiles of EPA+DHA were 40, 84, 151, and 234 mg/d. Medians of fish consumption in quartiles were 1.1, 4.2, 10.7, and 17.3 g/d. Compared with the lowest quartile of EPA+DHA, participants in the top quartile had a 49% lower risk of fatal CHD (95% CI: 6-73%) and a 62% lower risk of fatal MI (95% CI: 23-81%). We observed inverse dose-response relations for EPA+DHA intake and fatal CHD (P-trend = 0.05) and fatal MI (P-trend = 0.01). Results were similar for fish consumption. Nonfatal MI was not associated with EPA+DHA or fish intake. In conclusion, in populations with a low fish consumption, EPA+DHA and fish may lower fatal CHD and MI risk in a dose-responsive manner. Low intakes of EPA+DHA or fish do not seem to protect against nonfatal MI.

Background: The aim was to investigate whether multivariate coefficients of serum cholesterol in the prediction of coronary heart disease (CHD) deaths were similar across different cultures in a long-term follow-up., Design: Thirteen cohorts for a total of 10,157 men aged 40-59 years at entry, enrolled in seven countries (USA, Finland, the Netherlands, Italy, Serbia, Greece, Japan) were repeatedly examined and followed up for 40 years., Methods: Serum cholesterol measured at baseline, and then on repeated occasions, was studied, using multivariate models, in relation with the occurrence of CHD deaths during a 40-year follow-up., Results: Homogeneity of multivariate serum cholesterol coefficients was found considering cholesterol levels at baseline, as average of up to three measurements during the first 10 years, as average of up to six measurements in 35 years, using the time-dependent technique with up to three measurements in 10 years, and with up to six measurement in 35 years., Conclusion: The strength of the association between serum cholesterol and CHD death seems homogeneous across different cultures characterized by different levels of serum cholesterol and different absolute risk of CHD death.

Background: Little is known about the effects of dietary fiber intake on long-term mortality., Objective: We aimed to study recent and long-term dietary fiber intake in relation to coronary heart disease and all-cause mortality., Design: The effects of recent and long-term dietary fiber intakes on mortality were investigated in the Zutphen Study, a cohort of 1,373 men born between 1900 and 1920 and examined repeatedly between 1960 and 2000. During that period, 1,130 men died, 348 as a result of coronary heart disease. Hazard ratios were obtained from time-dependent Cox regression models., Results: Every additional 10 g of recent dietary fiber intake per day reduced coronary heart disease mortality by 17% (95% CI: 2%, 30%) and all-cause mortality by 9% (0%, 18%). The strength of the association between long-term dietary fiber intake and all-cause mortality decreased from age 50 y (hazard ratio: 0.71; 95% CI: 0.55, 0.93) until age 80 y (0.99; 0.87, 1.12). We observed no clear associations for different types of dietary fiber., Conclusions: A higher recent dietary fiber intake was associated with a lower risk of both coronary heart disease and all-cause mortality. For long-term intake, the strength of the association between dietary fiber and all-cause mortality decreased with increasing age.

Aims: To assess the relationship between fish consumption or eicosapentaenoic acid (EPA)+docosahexaenoic acid (DHA) intake from fish, and (sudden) coronary death., Methods and Results: The impact of recent and long-term fish consumption and EPA+DHA intake on (sudden) coronary death was investigated in the Zutphen Study, a cohort of 1373 men born between 1900 and 1920, and examined repeatedly between 1960 and 2000. Hazard ratios were obtained from time-dependent Cox regression models. The associations between long-term fish consumption, EPA+DHA intake, and (sudden) coronary death were stronger than those of recent consumption. Long-term fish consumption was inversely associated (borderline significant) with coronary heart disease (CHD) death; however, the strength of the association decreased from age 50 [HR: 0.32 (95% CI: 0.13-0.80)] until age 80 [HR: 1.34 (0.58-3.12)]. For men with a daily EPA+DHA intake from fish below 250 mg compared with no intake, CHD death risk was reduced to the same extent as for men with a daily intake above 250 mg (P-value for trend: 0.27). Moreover, long-term fatty-fish consumption lowered the risk of sudden coronary death [HR: 0.46 (0.27-0.78)]., Conclusion: The strength of the association between long-term fish consumption and CHD death decreased with increasing age. Fatty-fish consumption lowered sudden coronary death risk. There was no clear dose-response relationship between EPA+DHA intake and (sudden) coronary death.

Background: Oxidative stress may accelerate ageing and increase the risk of chronic diseases, such as coronary heart disease (CHD). We assessed differences in oxidative stress, and iron and antioxidant status between elderly men living in Mediterranean southern Europe (Crete, Greece) and northern Europe (Zutphen, The Netherlands)., Design: A cross-sectional study using data from two cohorts of the Seven Countries Study., Methods: Non-fasting blood samples were drawn in 2000 from 105 men from Crete and 139 men from Zutphen, all aged 79 years or over. All assays were performed in the same laboratory., Results: After multiple adjustments, serum levels of the markers of oxidative stress were lower in Cretan men than in men from Zutphen, as indicated by lower mean levels of hydroperoxides (33.2 versus 57.3 micromol/l; P=0.005) and gamma-glutamyltransferase (20.3 versus 26.1 U/l; P=0.003). The most pronounced difference in iron status was a twofold lower mean serum ferritin level in Cretan men (69.8 microg/l) compared with men from Zutphen (134.2 microg/l; P<0.0001). Men from Crete had consistently higher plasma levels of major plasma antioxidants than the Zutphen men, including a nearly fourfold higher mean level of lycopene (15.3 versus 4.1 microg/100 ml; P<0.0001)., Conclusion: Elderly men from Crete had consistently lower levels of the indicators of oxidative stress and iron status and higher concentrations of major antioxidants than men from Zutphen. These differences may contribute to the lower rate of CHD and total mortality that has been observed in this cohort of Cretan men.

The authors aimed to quantify the effects of current systolic blood pressure (SBP) and serum total cholesterol on the risk of mortality in comparison with SBP or serum cholesterol 25 years previously, taking measurement error into account. The authors reanalyzed 35-year follow-up data on mortality due to coronary heart disease and stroke among subjects aged 65 years or more from nine cohorts of the Seven Countries Study. The two-step method of Tsiatis et al. (J Am Stat Assoc 1995;90:27-37) was used to adjust for regression dilution bias, and results were compared with those obtained using more commonly applied methods of adjustment for regression dilution bias. It was found that the commonly used univariate adjustment for regression dilution bias overestimates the effects of both SBP and cholesterol compared with multivariate methods. Also, the two-step method makes better use of the information available, resulting in smaller confidence intervals. Results comparing recent and past exposure indicated that past SBP is more important than recent SBP in terms of its effect on coronary heart disease mortality, while both recent and past values seem to be important for effects of cholesterol on coronary heart disease mortality and effects of SBP on stroke mortality. Associations between serum cholesterol concentration and risk of stroke mortality are weak.

Background: Plant lignans are converted to enterolignans that have antioxidant and weak estrogen-like activities, and therefore they may lower cardiovascular disease and cancer risks., Objective: We investigated whether the intakes of 4 plant lignans (lariciresinol, pinoresinol, secoisolariciresinol, and matairesinol) were inversely associated with coronary heart disease (CHD), cardiovascular diseases (CVD), cancer, and all-cause mortality., Design: The Zutphen Elderly Study is a prospective cohort study in which 570 men aged 64-84 y were followed for 15 y. We recently developed a database and used it to estimate the dietary intakes of 4 plant lignans. Lignan intake was related to mortality with the use of Cox proportional hazards analysis., Results: The median total lignan intake in 1985 was 977 microg/d. Tea, vegetables, bread, coffee, fruit, and wine were the major sources of lignan. The total lignan intake was not related to mortality. However, the intake of matairesinol was inversely associated with CHD, CVD, and all-cause mortality (P

Objective: To explore whether "typical" coronary heart disease (CHD) such as fatal myocardial infarction and sudden death relate to major cardiovascular risk factors in the same way as the "atypical" CHD, such as fatal heart failure and chronic arrhythmias., Design and Setting: Ten cohorts (6633 cardiovascular disease-free men, aged 40-59) in five European countries were examined, age and three major risk factors were measured (systolic blood pressure, serum cholesterol, and smoking habits) and 35-year mortality data were collected. Proportional hazard models were solved with typical and atypical CHD deaths treated separately., Results: Death rates from typical and atypical CHD were inversely related among the five countries. Mean age at death was significantly higher for atypical than typical (75.8 versus 71.6 years; p < 0.001). In the multivariate analysis conducted on pools of 5 countries (adjusted for countries), the relationship of risk factors with typical CHD was direct and significant for age (hazard ratio-HR-for 5 years of age 1.44 (95% CI 1.36-1.52)), systolic blood pressure (HR for 20 mm Hg, 1.39 (95% CI 1.32-1.47)), serum cholesterol (HR for 1 mmol/l of 1.22 (95% CI 1.16-1.27)) and smoking habits (HR smokers versus non-smokers of 1.39 (95% CI 1.24-1.57)). For atypical CHD, age had a larger HR of 2.27 (95% CI 2.05-2.52), systolic blood pressure had a smaller HR of 1.28 (95% CI 1.16-1.41), serum cholesterol had an inverse non-significant HR of 0.90 (0.58-1.58) and smoking habits had a larger HR of 1.54 (95% CI 1.26-1.89)., Conclusions: Age and serum cholesterol were differently related with typical and atypical CHD deaths, suggesting different etiologies for these coronary diseases.

During the last century much evidence has accumulated to suggest that from a public health perspective the type of fat is more important than the amount of fat. Saturated and trans-fatty acids increase and both n-6 and n-3 PUFA decrease the risk of CHD. Most of the knowledge about the effects of dietary fatty acids on CHD risk is based on observational studies and controlled dietary experiments with intermediate end points (e.g. blood lipoprotein fractions). Information from high-quality randomised controlled trials on fatty acids and CHD is lacking. The Netherlands Institute for Public Health has calculated the potential health gain that can be achieved if the fatty acid composition of the current Dutch diet is replaced by the recommended fatty acid composition. The recommendations of The Netherlands Health Council are: saturated fatty acids <10% energy intake; trans-fatty acids <1% energy intake; fish consumption (an indicator of n-3 PUFA) once or twice weekly. Implementation of this recommendation could reduce the incidence of CHD in The Netherlands by about 25,000/year and the number of CHD-related deaths by about 6000/year and increase life expectancy from age 40 years onwards by 0.5 year. These projections indicate the public health potential of interventions that modify the fatty acid composition of the diet.

Context: Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke., Objective: To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data., Data Sources: Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators., Study Selection: All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded., Data Extraction: Individual records were provided on each of 154,211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13,210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias., Data Synthesis: Within each age group considered (40-59, 60-69, and > or =70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design., Conclusions: In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.

Background: Guidelines for lifestyle and dietary modification in patients with coronary artery disease (CAD) are mainly supported by evidence from general population studies. CAD patients, however, differ from the general population in age (older) and treatment with preventive drugs. This review seeks to provide evidence for a prognostic benefit of lifestyle and dietary recommendations from studies in CAD patients., Methods and Results: A literature search was performed on the effect of lifestyle and dietary changes on mortality in CAD patients. Prospective cohort studies and randomized controlled trials of patients with established CAD were included if they reported all-causes mortality and had at least 6 months of follow-up. The effect estimates of smoking cessation (relative risk [RR], 0.64; 95% CI, 0.58 to 0.71), increased physical activity (RR, 0.76; 95% CI, 0.59 to 0.98), and moderate alcohol use (RR, 0.80; 95% CI, 0.78 to 0.83) were studied most extensively. For the 6 dietary goals, data were too limited to provide reliable effect size estimates. Combinations of dietary changes were associated with reduced mortality (RR, 0.56; 95% CI, 0.42 to 0.74)., Conclusions: Available studies show convincingly the health benefits of lifestyle changes in CAD patients. Effect estimates of combined dietary changes look promising. Future studies should confirm these findings and assess the contribution of the individual dietary factors.

Background: The purpose of this study was to explore the duration of the association of major coronary risk factors measured on a single occasion with coronary heart disease (CHD) deaths during 40 years in a population sample of middle-aged men., Design: Measurement of age, systolic blood pressure, serum total cholesterol, and cigarette smoking was made on a single occasion in 2376 cardiovascular disease free men, aged 40-59, belonging to the US Railroad cohort of the Seven Countries Study enrolled in the late 1950s. During 40 years of follow up 627 men died from typical CHD (sudden death coronary death or definite myocardial infarction)., Methods: Eight partitioned proportional hazards models were solved, one for each independent 5-year block of follow up, to predict the risk of CHD death. Eight 5-year partitioned hazard scores, derived from the coefficients, were cumulated for each risk factor., Results: The resulting curves showed a regularly increasing time trend in risk for coronary deaths as a function of serum cholesterol, systolic blood pressure and cigarette smoking, for the first 30-35 years of follow up followed by a loss of predictive power thereafter. The curves fit straight lines, with large squared correlation coefficients ranging from 0.96 to 0.99. There was a relatively constant strength in the association of risk factors levels with events, which are predicted irrespective of the distance from risk factor measurements., Conclusions: Measurement of major coronary risk factors taken on a single occasion in middle-aged men maintained a regular and almost monotonic relationship with the subsequent occurrence of CHD deaths for at least 30-35 years of follow up.

Vitamin E is a fat-soluble antioxidant and is possibly involved in the prevention of coronary heart disease by inhibiting oxidative modification of LDL cholesterol. The results of studies on the association between vitamin-E intake and coronary heart disease are inconsistent in observational studies and absent in large-scale intervention studies. This may be the consequence of confounding in observational studies and imperfections in the design of intervention trials. Another explanation is that vitamin E may only function protectively in the presence of sufficient co-antioxidants. At present, there is no evidence that vitamin E lowers the risk of coronary heart disease.

The results of prospective studies on the relations between the plasma concentration of total homocysteine (tHcy) and B-vitamins, on the one hand, and coronary heart disease (CHD) mortality, on the other hand, are inconclusive and scarce considering the relation with B-vitamins. We prospectively determined these relations in a case-cohort study. The full-cohort existed in approximately 36,000 Dutch adults aged 20-59 years at baseline. The statistical analyses were done with a random sample from the cohort (n=630) complemented with all subjects who died of CHD (n=102) during a mean follow-up of 10.3 years. All subjects reported the absence of cardiovascular diseases (CVDs) at baseline. The plasma concentrations of tHcy, folate, PLP, and vitamin B12 were determined in samples obtained at baseline. Men with a tHcy concentration in the highest tertile (T3) compared with men in the lowest tertile (T1) had a relative risk (RR) of 1.14 for CHD (95% confidence interval (CI): 0.50, 2.61) after adjusting for age, study center, hypertension, HDL and total cholesterol, smoking, and creatinine. For women, this RR was 2.04 (95% CI: 0.48, 8.62). For each 5 micromol/l increase in tHcy, the RR of CHD was 1.03 (95% CI: 0.83-1.29) for men and women combined. In women only, high folate levels were associated with a statistically significant protection of fatal CHD (T3 versus T1; RR: 0.22, 95% CI: 0.06, 0.87). Plasma PLP (B6) and vitamin B12 concentrations were not associated with CHD risk. We conclude that elevated tHcy concentrations do not seem to be a risk factor for CHD mortality in these relatively young healthy Dutch subjects free of baseline CVD. Higher folate concentrations may be protective of CHD, but this needs confirmation.

The 'accelerated failure time model' (AFT) was tested in the 25-year experience of the Seven Countries Study, to describe the shape of hazard for coronary heart disease (CHD) mortality during long-term follow-up. Sixteen cohorts of men aged 40-59 at entry were enrolled in eight countries (USA, Finland, The Netherlands, Italy, Croatia, Serbia, Greece and Japan) for a total of 12,763 subjects. Risk factors were measured and CHD mortality data collected during 25 years. The AFT incorporating the Weibull survival distribution was applied to the pooled cohorts of each country, with CHD mortality as endpoint. Cumulative hazards and the annual hazard for CHD mortality were estimated during 25 years and compared among countries. The annual hazard for CHD in 25 years tended to reduce relatively or flatten out in the northern American and northern European countries, exponentially increased in Serbia and Japan, and increased moderately in the other countries of southern Europe. Positive correlations were found between the shape of the hazard curve and population mean risk factor changes (serum cholesterol and systolic blood pressure) observed during the first 10 years follow-up. The Japanese group was an outlier. The countries with the largest relative decline in the annual hazard function were the same where, during the same historical period, the largest decreases in official death rates from CHD were recorded and vice versa. The curve shape in the annual hazard for CHD mortality in different countries seems related to changes in mean levels of serum cholesterol and systolic blood pressure.

There are strong indications that eating (fatty) fish or n-3 fatty acids from fish reduces the risk of fata coronary heart disease (CHD). Observational studies in the general population show that consumption of moderate amounts of fish or n-3 fatty acids from fish are associated with a lower risk of fatal coronary heart disease and in particular sudden cardiac death. The most plausible hypothesis is that n-3 fatty acids reduce the risk of CHD mortality via anti-arrhythmic effects. Two clinical intervention trials show that prescription of fish or n-3 fatty acids to patients with prior myocardial infarction is effective in preventing mortality due to CHD. Ongoing trials will have to prove the effectiveness of a low dose of n-3 fatty acids and show that the underlying mechanism involves a protective effect against life-threatening arrhythmias. In addition to other recommendations for a healthier diet and lifestyle, consumption of one or two fatty fish meals a week is a highly effective and safe measure to reduce CHD mortality in both the general population and patients.

Background: Data on the relation between alpha-linolenic acid intake and coronary artery disease (CAD) are limited. Other dietary components appear to modify the reported relation between alpha-linolenic acid intake and CAD., Objective: We examined whether dietary alpha-linolenic acid intake was inversely associated with risk of CAD., Design: We prospectively studied 667 men aged 64-84 y from the Zutphen Elderly Study who were free of CAD at baseline. Dietary intake was assessed by using a cross-check dietary history method., Results: During the 10-y follow-up, we documented 98 cases of CAD. After adjustment for age, standard coronary risk factors, and intake of trans fatty acids and other nutrients, alpha-linolenic acid intake was not significantly associated with CAD risk. The relative risk of CAD for the highest compared with the lowest tertile of alpha-linolenic acid intake was 1.68 (95% CI: 0.86, 3.29). alpha-Linolenic acid intake from sources containing trans fatty acids was also nonsignificantly, yet positively, associated with CAD risk. alpha-Linolenic acid intake from foods that did not contain trans fatty acids was not associated with CAD risk, the relative risk of CAD for the highest compared with the lowest tertile was 1.15 (95% CI: 0.63, 2.11)., Conclusion: We did not observe a beneficial effect of dietary alpha-linolenic acid intake on the risk of 10-y CAD incidence. Investigating this hypothesis was complicated by the association between intakes of alpha-linolenic acid and trans fatty acids. Given the results of current prospective studies, a protective cardiac effect of alpha-linolenic acid is questionable.

Background: Evidence on the relation between trans fatty acid intake and coronary heart disease is limited. We investigated this relation in a Dutch population with a fairly high trans fatty acid intake, including trans fatty acids from partly hydrogenated fish oils., Methods: We prospectively studied 667 men of the Zutphen Elderly Study aged 64-84 years and free of coronary heart disease at baseline. We used dietary surveys to establish the participants' food consumption patterns. Information on risk factors and diet was obtained in 1985, 1990, and 1995. After 10 years of follow-up from 1985-95, there were 98 cases of fatal or non-fatal coronary heart disease., Findings: Between 1985 and 1995, average trans fatty acid intake decreased from 4.3% to 1.9% of energy. After adjustment for age, body mass index, smoking, and dietary covariates, trans fatty acid intake at baseline was positively associated with the 10-year risk of coronary heart disease. The relative risk for a difference of 2% of energy in trans fatty acid intake at baseline was 1.28 (95% CI 1.01-1.61)., Interpretation: A high intake of trans fatty acids (all types of isomers) contributes to the risk of coronary heart disease. The substantial decrease in trans fatty acid intake, mainly due to industrial lowering of trans contents in Dutch edible fats, could therefore have had a large public-health impact.

Objectives: Ten-year coronary heart disease (CHD) mortality in elderly male cohorts in three European countries was evaluated as a function of silent resting Minnesota Code electrocardiographic (ECG) findings found at baseline., Methods and Results: Men aged 65-84 at entry were enrolled, examined and followed up for 10 years in 5 cohorts of three countries: Finland (N=716), the Netherlands (N= 887), and Italy (N = 682). Men with symptomatic angina pectoris, a documented history of myocardial infarction or heart failure were excluded from analysis, leaving 505 men in Finland, 713 in the Netherlands and 567 in Italy. ECG abnormalities were arranged in different groupings. Multivariate analyses adjusted ECG prediction of CHD mortality for cohort, and baseline age, systolic blood pressure, serum cholesterol, body mass index and cigarette smoking., Results: Silent ECG abnormalities of presumed severity were found in more than half of these elderly men, with higher prevalence in Finland, compared to the other two countries. Adjusted hazards ratios for CHD deaths as a function of major single or combined ECG abnormalities, such as QQS and ST-T abnormalities, arrhythmia, definite and possible myocardial infarction and an operative definition of ischaemia, are generally similar across areas varying according to severity from around 1.5 to almost 4. Groupings of minor and major ECG abnormalities in the pooled countries gave significant relative risks of 1.79 and 3.12 respectively, compared to the group without or with marginal abnormalities. Sensitivity and positive predictive value were low, while specificity was high., Conclusions: Silent ECG abnormalities in elderly people are common and they carry a high risk of coronary death in the next 10 years, with relative risk ranging from around 1.5 to almost 4 or more depending upon severity and combination of findings.

From experimental studies, the hypothesis is derived that the amino acid arginine, the precursor of NO, could restore the impaired endothelial function and increased platelet activation observed in atherosclerosis. We investigated whether dietary intake of arginine is associated with reduced coronary heart disease risk in elderly persons. The study population consisted of 806 men aged 64 to 84 years at baseline who participated in the Zutphen Elderly Study, a population-based cohort followed up for 10 years. Information about habitual food consumption was collected by use of the cross-check dietary history method. Ninety (11.2%) of the 806 men died from coronary heart disease. Mean+/-SD baseline arginine intake was 4. 35+/-1.07 g/d. Meat was the main source of arginine intake (37.1%), followed by bread (13.1%) and milk and milk products (12.1%). Arginine intake was not associated with coronary heart disease mortality. After adjustment for age, the relative risk (RR) for the medium tertile of arginine intake was 0.72 (95% CI 0.44 to 1.18), and the RR for the highest tertile was 0.71 (95% CI 0.43 to 1.19, P: for trend=0.19) compared with the lowest tertile of arginine intake. After additional adjustment for history of coronary heart disease and diabetes mellitus, energy intake, body mass index, smoking habit, physical activity, and other relevant dietary and biological risk factors, the RR was 1.86 (95% CI 1.06 to 3.27) for the medium intake and 1.56 (95% CI 0.83 to 2.93) for the highest intake (P: for trend=0.17). These results do not support the hypothesis that dietary arginine intake lowers the risk of coronary heart disease mortality.

Objective: A systematic reanalysis of 10 year coronary heart disease incidence data from the northern and the southern European cohorts of the seven countries study, to contribute indirectly to the production of a European coronary risk chart., Design and Setting: Men aged 40-59 years at entry were studied in three northern European cohorts based in Finland and Netherlands (n = 2213); and in 10 southern European cohorts based in Italy, former Yugoslavia, and Greece (n = 5897). Multiple logistic models for the prediction of coronary deaths, coronary incidence (hard criteria), and coronary incidence (any criterion) were solved for the two geographical groups and their pool. Risk factors fed into the models were age, systolic blood pressure, serum total cholesterol, and cigarette smoking., Results: 10 year coronary heart disease mortality and incidence were higher in northern than in southern Europe, with ratios around 2.65. Ratios among the three coronary heart disease manifestations were identical in the two cultural groupings. Coefficients of the multiple logistic models were similar and not significantly different between the two groupings. When applying the coefficients back to the same or the opposite population, the relative risk was large and similar in the different cultures. Relative risk was larger for more severe coronary heart disease manifestations. The absolute risk was overestimated when applying the northern European model to southern European populations and vice versa, with ratios of about 1.5 and 0.5, respectively. Coronary risk charts created to reproduce the shape of those incorporated in recent European guidelines confirmed the excess of absolute risk in the northern compared with the southern European cohorts, all else being equal., Conclusions: In theory, a more appropriate European coronary risk chart could be produced by adopting coefficients to correct for different background incidence rates in different cultures. Other coefficients could appropriately be used to transform mortality risk into incidence risk.

Objective: To examine whether a high dietary glycemic index is associated with hyperinsulinemia, hyperglycemia, dyslipidemia and coronary heart disease (CHD) risk in elderly men., Design: Prospective study of incidence of major CHD (non-fatal myocardial infarction or death due to CHD) between 1985 and 1995 in 646 men, and a cross-sectional analysis of metabolic risk factors in 1990 in 394 men., Setting: Population based study in the Dutch town Zutphen., Subjects: Men aged 64-84 y in 1985 without a history of CHD or diabetes, whose diet was assessed with the cross-check dietary history method., Results: The dietary glycemic index was positively correlated with consumption (g carbohydrate) of wheat bread (r=0.47) and sugar products (r=0.41) and inversely with fruit (r=-0.37) and milk (r=-0.40) consumption. During 4527 person-years of follow-up, 94 cases of CHD were documented. The risk ratio for CHD was 1.11 (95% CI, 0.66-1.87) for the highest as compared to the lowest tertile of glycemic index after correction for age, body mass index, physical activity, cigarette smoking, and dietary factors (P (trend)=0.70). Furthermore, the glycemic index was not appreciably associated with blood concentrations of total cholesterol, HDL-cholesterol, triacylglycerols or (fasting or postload) insulin or glucose., Conclusions: Our findings do not support the hypothesis that a high-glycemic-index diet unfavorably affects metabolic risk factors or increases risk for CHD in elderly men without a history of diabetes or CHD.

Fish consumption seems to protect against death from coronary heart disease (CHD). If this association is due to n-3 polyunsaturated fatty acids, especially fatty fish may be responsible for this protective effect. The association between total, lean, and fatty fish consumption and the risk of CHD mortality was examined in 1,088 Finnish, 1,097 Italian, and 553 Dutch men participants in the Seven Countries Study who were aged 50-69 years and free of CHD around 1970. After 20 years of follow-up, 242 (22.2%) men in Finland, 116 (10.6%) men in Italy, and 105 (19.0%) men in the Netherlands had died of CHD. Cox proportional hazards analysis showed no association between total fish consumption and CHD mortality. After adjustments were made for age, body mass index, smoking, energy intake, and relevant dietary variables, the pooled relative risk for the highest quartile of total fish compared with no fish consumption in the three countries was 1.08 (95% confidence interval: 0.76, 1.53). Lean fish consumption also was not associated with CHD mortality in any country. Fatty fish compared with non-fatty-fish consumption was associated with lower CHD mortality; the adjusted, pooled relative risk for fatty fish consumers was 0.66 (95% confidence interval: 0.49, 0.90). These data suggest that especially fatty fish is protective against CHD mortality.

We studied the relation between serum total and high-density lipoprotein (HDL) cholesterol and 10-year coronary heart disease mortality in elderly men in different European countries. The Finland, Italy and the Netherlands Elderly (FINE) Study is a prospective follow-up study in 2,132 elderly men ages 65-84 years in Finland, the Netherlands, and Italy. We estimated relative risks using Cox proportional hazard analysis with time-dependent covariates. Total cholesterol was positively related to coronary heart disease mortality in all three countries. The combined relative risk for the total population of the FINE Study was 1.17 (95% confidence interval = 1.06-1.29) for each 1.00 mmol/liter increase in total cholesterol. HDL cholesterol was inversely related to coronary heart disease mortality in Finland, but not in the Netherlands and Italy. In Italy we noted an interaction among HDL cholesterol, body mass index, and alcohol intake, with an inverse association for HDL cholesterol in lean men who drank <40 gm of alcohol daily and a positive association for HDL cholesterol among overweight men who drank > or =40 gm of alcohol per day. Serum total cholesterol remains an important predictor of coronary heart disease mortality in elderly men in different European countries. The effect of HDL cholesterol differed among the three countries.

Background: Elevated blood pressure is known to be a risk factor for death from coronary heart disease (CHD). However, it is unclear whether the risk of death from CHD in relation to blood pressure varies among populations., Methods: In six populations in different parts of the world, we examined systolic and diastolic blood pressures and hypertension in relation to long-term mortality from CHD, both with and without adjustment for variability in blood pressure within individual subjects. Blood pressure was measured at base-line in 12,031 men (age range, 40 to 59 years) who were free of CHD. During 25 years of follow-up, 1291 men died from CHD., Results: At systolic and diastolic blood pressures of about 140 and 85 mm Hg, respectively, 25-year rates of mortality from CHD (standardized for age) varied by a factor of more than three among the populations. Rates in the United States and northern Europe were high (approximately 70 deaths per 10,000 person-years), but rates in Japan and Mediterranean southern Europe were low (approximately 20 deaths per 10,000 person-years). However, the relative increase in 25-year mortality from CHD for a given increase in blood pressure was similar among the populations. The overall unadjusted relative risk of death due to CHD was 1.17 (95 percent confidence interval, 1.14 to 1.20) per 10 mm Hg increase in systolic pressure and 1.13 (95 percent confidence interval, 1.10 to 1.15) per 5 mm Hg increase in diastolic pressure, and it was 1.28 for each of these increments after adjustment for within-subject variability in blood pressure., Conclusions: Among the six populations we studied, the relative increase in long-term mortality due to CHD for a given increase in blood pressure is similar, whereas the absolute risk at the same level of blood pressure varies substantially. If the absolute risk of CHD is used as an indication for antihypertensive therapy, these findings will have major implications for treatment in different parts of the world.

We investigated the impact of family history of myocardial infarction on 12-year coronary heart disease mortality. Men and women with a family history had an increased risk for coronary heart disease death, irrespective of other risk factors (RR = 1.58; 95% CI = 1.17-2.13 and RR = 2.12; 95% CI = 1.11-4.05, respectively). Women with a family history seemed to be more susceptible to the detrimental effects of smoking; not to the effects of other risk factors. We found no effect modification by family history in men.

In the Seven Countries Study, associations between the intake of food-groups and 25-year mortality from coronary heart disease (CHD, defined as sudden coronary death or fatal myocardial infarction) were investigated. Baseline surveys were carried out between 1958 and 1964. A number of individual characteristics were measured in 12,763 middle-aged men belonging to 16 cohorts in seven countries (USA, Finland, The Netherlands, Italy, former Yugoslavia, Greece and Japan). Dietary information was collected in sub-samples using the weighed record method. Vital status of all participants was verified at regular intervals during 25 years of follow-up and the underlying cause of death was adjudicated. Eighteen different food-groups and combinations were considered for comparison among cohorts. Large differences in food-group consumption were seen, with high consumption of dairy products in Northern Europe, meat in the USA, vegetables, legumes, fish, and wine in Southern Europe, and cereals, soy products, and fish in Japan. Population death rates from CHD showed large differences, ranging from 268 per 1000 in East Finland to 25 per 1000 in Crete, Greece. Animal food-groups were directly correlated, and vegetable food-groups (except potatoes) as well as fish and alcohol were inversely correlated with CHD mortality. Univariate analysis showed significant positive correlation coefficients for butter (R = 0.887), meat (R = 0.645), pastries (R = 0.752), and milk (R = 0.600) consumption, and significant negative correlation coefficients for legumes (R = -0.822), oils (R = -0.571), and alcohol (R = -0.609) consumption. Combined vegetable foods (excluding alcohol) were inversely correlated (R = -0.519), whereas combined animal foods (excluding fish) were directly correlated (R = 0.798) with CHD death rates. Multivariate stepwise analysis selected butter, lard + margarine and meat as significant predictors and produced an R2 of 0.922. These findings were confirmed by factor analysis. These cross-cultural analyses are consistent with the hypothesis that dietary patterns are important determinants of differences in population CHD death rates, and confirm the opposite effects on apparent risk of animal and vegetable foods.

Oxidized low density lipoproteins (LDL) play a major role in the development of atherosclerosis. Saturated fatty acids, especially fatty acids with 12-16 carbon atoms, are the most important determinants of the LDL cholesterol level. The LDL lipoprotein fraction can be oxidized by, e.g., smoking. Oxidative damage of LDL lipoproteins can be prevented by nutritive, e.g., vitamin E, and nonnutritive antioxidants, e.g., flavonoids. It can therefore be hypothesized that fatty acids and antioxidants are important determinants of coronary heart disease (CHD). There is a large body of evidence from prospective studies that LDL cholesterol-lowering is associated with a lower CHD risk. The evidence for a protective effect of antioxidants on CHD risk is much weaker and is most promising for vitamin E and flavonoids. The Seven Countries Study showed that at the population level saturated fat, cigarette smoking, and flavonoids are important determinants of long-term CHD mortality. These results suggest that a diet low in saturated fat and rich in antioxidants in combination with no smoking is associated with low CHD risk.

Hyperhomocysteinemia is an independent risk factor for atherosclerotic disease in the middle-aged. We investigated whether a high serum homocysteine level is a risk factor for vascular disease in 878 elderly men (mean age at baseline, 71.5 years; range, 64 to 84 years) in a population-based, representative cohort followed up for 10 years in Zutphen, the Netherlands. Thirty-one percent had nonfasting homocysteine levels >/=17 micromol/L. After adjustment for other major risk factors, high homocysteine levels at baseline (the third compared with the first tertile) were associated with an increased baseline prevalence of myocardial infarction (odds ratio [OR], 1.81; 95% confidence interval [CI], 1.07 to 3.08; P for trend, 0.03) and with a marginally significant increase in the risk of dying of coronary heart disease (relative risk [RR], 1.58; 95% CI, 0.93 to 2.69; P for trend, 0.09) but not with an increased risk of first-ever myocardial infarction. In addition, high homocysteine levels at baseline were associated with an increased baseline prevalence of stroke (OR, 4.61; 95% CI, 1.79 to 11.89; P for trend, 0.002) and with an increased risk of dying of cerebrovascular disease in subjects without hypertension (RR, 6.18; 95% CI, 2.28 to 16.76) but not in those with hypertension. High homocysteine levels were associated with an increased risk of first-ever stroke among normotensive subjects that was not statistically significant (RR, 1. 77 [95% CI, 0.83 to 3.75; P for trend, 0.14]). In a general population of elderly men, a high homocysteine level is common and is strongly associated with the prevalence of coronary heart disease and cerebrovascular disease. It is a strong predictive factor for fatal cerebrovascular disease in men without hypertension but less so for coronary heart disease.

To test the hypothesis that chronic infection with Chlamydia pneumoniae, Helicobacter pylori or cytomegalovirus is associated with coronary heart disease risk in elderly men, a nested case-control study in a cohort investigated in 1985 and 1990 in the town of Zutphen, The Netherlands, was designed. Fifty-four cases with a first diagnosed coronary event between 1985 and 1990, and 108 age-matched control subjects free of coronary heart disease during follow up were included in the study. The overall prevalence of antibodies to cytomegalovirus was 74.7%, to H. pylori 75.9% and to C. pneumoniae 84.0%. A high level of antibodies to C. pneumoniae was associated with an increased coronary heart disease risk (OR = 2.76; 95% CI = 1.31-5.81). This association was stronger in cases developing both myocardial infarction and angina pectoris, than in cases developing only one of these. This association was independent of potential confounders. Antibodies to cytomegalovirus or H. pylori were not associated with coronary heart disease risk. These results support the hypothesis of a role of chronic C. pneumoniae infections in the immunopathogenesis of atherosclerosis.