Daan Kromhout

Cardiovascular risk factors and dementia mortality: 40 years of follow-up in the Seven Countries Study

Previous research shows that cardiovascular risk factors in mid-adulthood could increase the risk of dementia later in life, but studies with very long follow-up are still scarce. We assessed whether cardiovascular risk factors measured in midlife were associated with dementia mortality during a 40-year follow-up. 10,211 men, aged 40-59 at baseline, from 13 cohorts of the Seven Countries Study were followed for 40 years. Information on cardiovascular risk factors was obtained at baseline from questionnaires and a physical examination. Dementia death was assigned if there was any mention of dementia on the death certificate. Associations between cardiovascular risk factors and death from dementia were estimated through Cox proportional hazards models. We identified 160 dementia deaths during the follow-up. Smoking, hypercholesterolemia, high blood pressure, low forced vital capacity and previous history of cardiovascular disease at baseline were associated with a higher risk of death from dementia in the follow-up. The hazard ratio (HR) of dementia death among heavy smokers was 1.58 (95% confidence interval (CI) 1.03, 2.43) compared to non-smokers. Similarly, the HR (95% CI) among those with systolic BP>or=160 or diastolic BP>or=95 mm Hg compared to normotensives (<140/90) was 1.55 (1.02, 2.35). Individuals with the largest forced vital capacity had a lower risk of dying of dementia (HR 0.54, 95% CI 0.30, 0.98). Finally, total serum cholesterol was directly associated with higher risk of dementia mortality (p for trend=0.03). In men, cardiovascular risk factors in midlife are associated with increased risk of dementia death later in life.

Effects of n−3 fatty acids on depressive symptoms and dispositional optimism after myocardial infarction

BACKGROUND In patients who have experienced a myocardial infarction (MI), n-3 (omega-3) PUFA status is low, whereas the risk of depression is increased. OBJECTIVE The objective was to assess whether the plant-derived α-linolenic acid (ALA) and the fish fatty acids EPA and DHA would improve affective states. DESIGN In a secondary analysis of the randomized, double-blind, placebo-controlled Alpha Omega Trial, 4116 of 4837 (85.1%) patients (aged 60-80 y; 79.2% men) who had experienced an MI were included. Margarine spreads were used to deliver 400 mg EPA-DHA/d, 2 g ALA/d, both EPA-DHA and ALA, or a placebo for 40 mo. At 40 mo, the endpoints of depressive symptoms (15-item Geriatric Depression Scale) and dispositional optimism (a 4-item questionnaire and the Life Orientation Test-Revised) were analyzed by using a posttest-only design. RESULTS The 4 randomly assigned groups did not differ in baseline characteristics. ALA supplementation significantly increased plasma cholesteryl ester concentrations of ALA by 69%, and EPA-DHA supplementation increased plasma cholesteryl ester concentrations of EPA and DHA by 61% and 30%, respectively. Depressive symptoms or dispositional optimism did not differ between groups with the use of n-3 fatty acids compared with placebo at the 40-mo follow-up. The standardized mean (±SE) differences in depressive symptoms were as follows: for EPA-DHA plus ALA (n = 1009) compared with placebo (n = 1030), -0.025 ± 0.044 (P = 0.57); for EPA-DHA (n = 1007) compared with placebo, -0.048 ± 0.044 (P = 0.28); and for ALA (n = 1022) compared with placebo, -0.047 ± 0.044 (P = 0.29). CONCLUSIONS In patients who had experienced an MI, low-dose EPA-DHA supplementation, ALA supplementation, or a combination of both did not affect depressive symptoms and dispositional optimism. These findings are in accord with those from previous trials in individuals without psychopathology or without severe depressive symptoms. This trial was registered at clinicaltrials.gov as NCT00127452.

Respiratory function and other biological risk factors for completed suicide: 40 years of follow-up of European cohorts of the Seven Countries Study

BACKGROUND Prospective cohort studies on biological risk factors of completed suicide are scarce. We aimed to test which biological risk factors independently identify subjects at increased risk of suicidal death. METHODS In the prospective cohort of the Seven Countries Study, 5,321 middle-aged men from Finland, Serbia, Italy, and Greece were included. Completed suicide (ICD-8 codes E950-959) was assessed during 40 years of follow-up. Biological cardiovascular risk factors (including forced vital capacity [FVC] and height) were tested for their role as predictors in multivariable Cox models stratified by country. RESULTS There were 4518 deaths during follow-up, with 64 from suicide (1.4%). In univariable models, only FVC and height were strongly inversely related with suicide. Socio-economic status and being unmarried were potential confounders. In multivariable models taking these confounders into account, both a low FVC (0.30 for top vs. lowest quartile; 95% CI: 0.12-0.76; P=0.006 for trend) and a low FVC/height ratio (0.37 for top vs. lowest quartile; 95% CI: 0.17-0.82; P=0.004 for trend) were strongly inversely related with completed suicide. LIMITATIONS Information on proximal causes, such as prior suicidal ideation, emotional distress and depression, was lacking at baseline. CONCLUSIONS Poor respiratory function in middle-aged men was an independent risk factor for completed suicide.

Plasma ascorbic acid, a priori diet quality score, and incident hypertension: A prospective cohort study

Vitamin C may reduce risk of hypertension, either in itself or by marking a healthy diet pattern. We assessed whether plasma ascorbic acid and the a priori diet quality score relate to incident hypertension and whether they explain each other’s predictive abilities. Data were from 2884 black and white adults (43% black, mean age 35 years) initially hypertension-free in the Coronary Artery Risk Development in Young Adults Study (study year 10, 1995–1996). Plasma ascorbic acid was assessed at year 10 and the diet quality score at year 7. Eight-hundred-and-forty cases of hypertension were documented between years 10 and 25. After multiple adjustments, each 12-point (1 SD) higher diet quality score at year 7 related to mean 3.7 μmol/L (95% CI 2.9 to 4.6) higher plasma ascorbic acid at year 10. In separate multiple-adjusted Cox regression models, the hazard ratio of hypertension per 19.6-μmol/L (1 SD) higher ascorbic acid was 0.85 (95% CI 0.79–0.92) and per 12-points higher diet score 0.86 (95% CI 0.79–0.94). These hazard ratios changed little with mutual adjustment of ascorbic acid and diet quality score for each other, or when adjusted for anthropometric variables, diabetes, and systolic blood pressure at year 10. Intake of dietary vitamin C and several food groups high in vitamin C content were inversely related to hypertension, whereas supplemental vitamin C was not. In conclusion, plasma ascorbic acid and the a priori diet quality score independently predict hypertension. This suggests that hypertension risk is reduced by improving overall diet quality and/or vitamin C status. The inverse association seen for dietary but not for supplemental vitamin C suggests that vitamin C status is preferably improved by eating foods rich in vitamin C, in addition to not smoking and other dietary habits that prevent ascorbic acid from depletion.

Spurious association between telomere length reduction over time and baseline telomere length

Ehrlenbach et al. found a linear relationship between baseline relative telomere length (RTL) and the decrease of RTL over 10 years (r1⁄4 0.674; P < 0.001). Similarly, others have reported on this relationship between the telomere attrition rate and the baseline telomere length and found largely similar associations. Likewise, when we correlated the RTL and delta RTL during 7 years of follow-up in 75 men from the Zutphen Elderly Study with an age range of 70–91 years, we found a largely identical association (r1⁄4 0.733; P < 0.001; EJ Giltay et al., unpublished results). We question whether this association is trivial. We used a random number generator to produce 510 baseline RTL values, similar to the number of pairs in the study of Ehrlenbach et al. A mean of 1.49 was aimed at for baseline values and 1.05 at 10-year follow-up, with distributions comparable to those presented in Table 1. Using these random numbers, we found a beta coefficient that was nearly similar to the beta coefficient that was presented in Table 2 (0.557 as compared with 0.589, respectively). Because baseline RTL (X) was used to calculate the RTL shortening rate (X–Y), the ‘dependent’ and ‘independent’ variables were functionally related. Pearson’s correlation coefficients using randomly generated factors can be estimated to be around 1/ˇ2, if baseline and outcome have equal variances. Therefore, it was to be expected that a linear regression model would best fit the data (as X was regressed on X–Y) and that an exceptional P-value of 2.3 10 90 was found (Table 2). We think that the slope of the regression line should have been tested against the slope of a no-effect line, instead of zero (i.e. a horizontal line). We think, therefore, that the reported association is explained neither by older cells having lower division rates nor by telomerase that acts preferentially on short telomeres as a special protection mechanism, as was suggested as potential explanations, but is merely a consequence of mathematical coupling. It seems more likely that the attrition rate of RTL is biologically independent of baseline RTL. Table 1 Hospital admissions for AMI (ICD-9: 410) in the Portuguese population during four international football competitions

Comparative ecologic relationships of saturated fat, sucrose, food groups, and a Mediterranean food pattern score to 50-year coronary heart disease mortality rates among 16 cohorts of the Seven Countries Study

Background/objectivesWe 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/methodsSixteen 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.ResultsEcologic 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.ConclusionsLong-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.

Type 2 Diabetes, Glucose Tolerance and Cardiovascular Diseases in the Seven Countries Study

The prevalence and incidence of type 2 diabetes (formerly called non-insulindependent diabetes) are increasing worldwide. The WHO predicts that the number of diabetic patients will increase from 143 million in 1997 to about 300 million in 2025 (1). A major determinant of diabetes is obesity and large increases in the prevalence of obesity were observed in the developed countries during the last decades of the 20thcentury and in developing countries more recently. Worldwide more than 250 million people are estimated to be obese (2). Another important determinant of diabetes is physical inactivity. There is now evidence from ecological, cross-sectional, and cohort studies that physical activity is inversely related to risk of type 2 diabetes (3).

Diet, Lifestyle and Prevention of Coronary Heart Disease the Integration of Observational and Experimental Evidence

Epidemiological studies, including the Seven Countries Study, have provided substantial evidence that diet is involved in the etiology of CHD. Observational epidemiology and controlled dietary intervention studies have shown that for prevention of CHD, fatty acid composition of the diet is of primary importance. A healthy diet should be low in saturated andtransfatty acids and should have an adequate amount of N-3 polyunsaturated fatty acids, and a balance between N-3 and N-6 polyunsaturated fatty acids. Dietary antioxidants and dietary fiber may be important, however, evidence for these factors is less impressive than that for fatty acids.

Risk Factors for Global Coronary Risk in Preventive and Clinical Cardiology

Epidemiological studies made clear by the late 1950s that blood cholesterol, blood pressure, and cigarette smoking were major risk factors for CHD. When firmly established in the 1970s, this led to the publication of the coronary risk handbook for the American Heart Association based on the Framingham Study risk chart (1), providing an aid for risk factor treatment in practice. However, we were into the 1990s before the concept of global risk based on multiple risk factors instead of single risk factors was widely accepted by the medical community and cardiologists. This was stimulated mainly by positive results of drug trials in primary and secondary prevention of CHD using statins for lowering cholesterol (2).

Fruit and Vegetable Consumption and Lung Cancer among Smokers in Finland, Italy and The Netherlands

Extended Abstract Unquestionably, cigarette smoking is the dominant risk factor for lung cancer. In addition, epidemiological studies consistently show an inverse association between fruit and vegetable consumption and lung cancer risk.1,2,3However, critics point at the possible role of residual confounding by smoking, and suggest that results from cohort studies may be less consistent compared with those from case-control studies.4Therefore, we examined the relationship between plant food consumption and lung cancer mortality in a cohort of men, focusing on smokers at baseline. Around 1970, dietary intake of Finnish, Italian and Dutch middle-aged men participating in the Seven Countries Study was assessed using a cross-check dietary history. Smoking habits and other lifestyle factors were determined by a standardised questionnaire. For 3108 men complete baseline information was available, of which 1578 were baseline smokers. During 25 years of follow-up, 187 lung cancer deaths occurred, of which 149 were smokers at baseline. Relative risks and 95% confidence intervals for consumption in country-specific tertiles were estimated by Cox proportional hazard analyses, and statistical significance was determined by two-sided tests. Risk estimates were calculated for the total study population and per country, both univariately and adjusted for potential confounders, including pack-years of smoking. Fruit consumption was inversely associated with lung cancer mortality in the total group of baseline smokers. Among Finnish smokers, lung cancer risk tended to be reduced in men with a medium or high fruit intake compared with those with the lowest fruit intake; however, estimates were not statistically significant. In Italian smokers, fruit consumption and lung cancer mortality were not related. Fruit consumption was only statistically significant inversely associated in the Dutch cohort. Stratifying the total cohort of smokers according to intensity of smoking, revealed the most pronounced relationship among the heaviest smokers. Vegetable intake and lung cancer mortality were not statistically significant related, neither in the total study population nor in the countries separately. In conclusion, this study shows a lower lung cancer risk among heavier smokers consuming more fruits. For vegetable consumption no such relationship was observed.