Anastasios Dontas

Vascular Factors and Risk of Dementia: Design of the Three-City Study and Baseline Characteristics of the Study Population

Objective: To describe the baseline characteristics of the participants in the Three-City (3C) Study, a study aiming to evaluate the risk of dementia and cognitive impairment attributable to vascular factors. Methods: Between 1999 and 2001, 9,693 persons aged 65 years and over, noninstitutionalized, were recruited from the electoral rolls of three French cities, i.e. Bordeaux, Dijon and Montpellier. Health-related data were collected during face-to-face interviews using standardized questionnaires. The baseline examination included cognitive testing and diagnosis of dementia, and assessment of vascular risk factors, including blood pressure measurements, ultrasound examination of the carotid arteries, and measurement of biological parameters (glycemia, total, high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, creatinemia); 3,442 magnetic resonance imaging (MRI) examinations were performed in subjects aged 65–79. Measurements of ultrasound, blood, and MRI parameters were centralized. Two follow-up examinations (at 2 and 4 years) were planned. Results: After exclusion of the participants who had subsequently refused the medical interview, the 3C Study sample consisted of 3,649 men (39.3%) and 5,645 women, mean age 74.4 years, with a relatively high level of education and income. Forty-two percent of the participants reported to be followed up for hypertension, about one third for hypercholesterolemia, and 8% for diabetes; 65% had elevated blood pressure measures (systolic blood pressure ≧140 or diastolic blood pressure ≧90). The proportion of Mini-Mental State Examination scores below 24 was 7% and dementia was diagnosed in 2.2% of the participants. Conclusion: Distribution of baseline characteristics of the 3C Study participants suggests that this study will provide a unique opportunity to estimate the risk of dementia attributable to vascular factors.

The Seven Countries Study : 2,289 deaths in 15 years

Among 11,579 men ages 40-59 without evidence of cardiovascular disease, 2,289 died in 15 years, 618 from coronary heart disease. The 15 cohorts in seven countries (four regions) differed in all-causes death rate, mainly reflecting great differences in coronary mortality. Among characteristics of entry, only mean blood pressure helped to explain cohort differences in all-causes death rate. Three-quarters of the variance in coronary death rate was accounted for by differences in mean serum cholesterol and blood pressure of the cohorts. The mortality risk for individuals was examined in each of the regions. For coronary death, age, serum cholesterol, blood pressure, and smoking were highly significant in all regions except Japan, where coronary deaths were too few for evaluation. Relative weight was not significant anywhere. Physical activity was significant only in southern Europe, where differences are associated with socioeconomic status. For all-causes death, age and blood pressure were highly significant risk factors in all regions as was smoking habit, except in Japan. Relative body weight tended to be a negative risk factor everywhere, significantly so in southern Europe. Expectations for coronary death from the experience in the United States and northern Europe greatly exceeded observed deaths in southern Europe for men of their age, serum cholesterol, blood pressure, smoking habits, physical activity, and relative weight. The reverse, prediction of coronary deaths in America and in northern Europe from the southern European experience, greatly underestimated the deaths observed. Similar cross-predictions between the United States and northern Europe were good for all-causes deaths, excellent for coronary deaths. Analysis of time trends in relationships of mortality to entry characteristics showed continued importance of age, blood pressure, and smoking and a tendency for the importance of cholesterol to fall in the last 5 years of follow-up.

Comparison of Multivariate Predictive Power of Major Risk Factors for Coronary Heart Diseases in Different Countries: Results from Eight Nations of the Seven Countries Study, 25-Year Follow-up

BACKGROUND It was hypothesized that among eight national groups of men aged 40-59 years enrolled in the Seven Countries Study, the multivariate coefficients of major risk factors predicting coronary heart disease mortality over 25 years would be relatively similar. MATERIALS AND METHODS Sixteen cohorts were located in eight nations and pooled, comprising one cohort in the USA, two in Finland, one in the Netherlands, three in Italy, two in Croatia (former Yugoslavia), three in Serbia (Yugoslavia), two in Greece and two in Japan, for a total of over 12000 subjects at entry. Coronary heart disease (CHD) mortality was defined as fatal myocardial infarction or sudden coronary death, and proportional hazard models were solved, for each country, with age, serum cholesterol level, systolic blood pressure and cigarette consumption as covariates. RESULTS The relationships between risk factors and CHD mortality were statistically significant for all risk factors and for all countries, except for age in Croatia and Japan, cholesterol in Croatia and Japan, systolic blood pressure in Serbia and Greece, and cigarette-smoking in the Netherlands, Croatia, Serbia and Greece. When comparing all pairs of coefficients (28 comparisons for each factor) significant differences were found on four occasions for age, on six occasions for cholesterol, on no occasion for blood pressure and on four occasions for cigarette-smoking. Other tests suggested a substantial homogeneity among multivariate coefficients. Estimates for pooled coefficients were: age, in years, 0.0570 (95% confidence limits 0.0465 and 0.0673); relative risk for 5 years 1.33 (95% confidence limits 1.26 and 1.40); serum cholesterol level in mg/dl, 0.0057 (95% confidence limits 0.0045 and 0.0069); relative risk for 40 mg/dl 1.31 (95% confidence limits 1.20 and 1.31); systolic blood pressure in mmHg, 0.0160, (95% confidence limits 0.0134 and 0.0185), relative risk for 20 mmHg 1.38 (95% confidence limits 1.31 and 1.45); cigarettes per day, 0.0220 (95% confidence limits 0.0170 and 0.0272); relative risk for 10 cigarettes per day 1.25 (95% confidence limits 1.18 and 1.31). CONCLUSIONS Great similarities were found in the multivariate coefficients of major coronary risk factors to CHD risk derived from population samples varying in CHD frequency.

Inter-cohort differences in coronary heart disease mortality in the 25-year follow-up of the seven countries study

Sixteen cohorts of men aged 40–59 years at entry were examined with the measurement of some risk factors and then followed-up for mortality and causes of death for 25 years. These cohorts were located in the USA (1 cohort), Finland (2), the Netherlands (1), Italy (3), the former Yugoslavia (5), Greece (2), and Japan (2), and included a total of 12,763 subjects.Large differences in age-adjusted coronary heart disease (CHD) death rates were found, with extremes of 45 per 1000 in 25 years in Tanushimaru, Japan, to 288 per 1000 in 25 years in East Finland. In general, higher rates were found in the US and Northern European cohorts as compared to the Southern European and Japanese cohorts. However, during the last 10 years of follow-up large increases of CHD death rates were found in some Yugoslavian areas. Out of 5 measured entry characteristics treated as age-adjusted levels (serum cholesterol, systolic blood pressure, cigarette smoking, body mass index and physical activity at work), only serum cholesterol was significant in explaining cohort differences in CHD death rates.Over 50% of the variance in CHD death rates in 25 years was accounted for by the difference in mean serum cholesterol. This association tended to decline with increasing length of follow-up, but this was due to the great changes in mean serum cholesterol in the two Jugoslavian cohorts of Velika Krsna and Zrenjanin. When these two cohorts were excluded the association increased with time.Changes in mean serum cholesterol between year 0 and 10 helped in explaining differences in CHD death rates from year 10 onward.It can be concluded that this study suggests that mean serum cholesterol is the major risk factor in explaining cross-cultural differences in CHD.

Seven Countries Study. First 20-Year Mortality Data in 12 Cohorts of Six Countries

Out of the original 16 cohorts in the Seven Countries Study on Cardiovascular Diseases, 12 population samples in six countries have reached the 20 year follow-up deadline. Data on mortality became fully available for a total of 8287 men aged 40-59 at entry examination (two cohorts in Finland, one in the Netherlands, three in Italy, two in Yugoslavia, two in Greece, and two in Japan). Death rates from CHD as well as from all causes follow the traditional falling north to south trend (18 fold between the extremes for CHD; 2.7 fold for total mortality). The differences in all causes mortality are, however, largely accounted for by the variation in CHD mortality. The mean entry levels of serum cholesterol and representative levels of the consumption of saturated fats, mono-unsaturated fats, poly-unsaturated fats and carbohydrates explain a large proportion of inter-cohort difference in CHD mortality (81% for saturated fats). By applying the proportional hazards model to the pools of national cohorts, with CHD deaths as end-point and five risk factors as covariates, only age and mean blood pressure are universally significant predictors of fatal events. Cholesterol, smoking habits, body mass index and physical activity play some part but not in all the pools. Age and mean blood pressure are also the only universal risk factors for all causes of death.

Twenty-five-year prediction of stroke deaths in the seven countries study: the role of blood pressure and its changes.

BACKGROUND AND PURPOSE This report explores the prediction of long-term stroke mortality in cohorts of the Seven Countries Study. METHODS Sixteen cohorts of men aged 40 to 59 years at entry were examined at years 0, 5, and 10, with mortality follow-up through 25 years. RESULTS Stroke death rates in 25 years were high in rural Serbia, Croatia, and Japan; intermediate in Italy, Greece, and urban Serbia; and low in Finland, the Netherlands, and the United States. Age and blood pressure were powerful predictors of 25-year stroke mortality in almost all cohorts and countries. Proportional hazards regression coefficients were .0232 increase in stroke death hazard per millimeter of mercury (t=14.60) for systolic blood pressure and .0409 (t=13.41) for diastolic blood pressure. Moderate blood pressure increases from low usual levels were associated with lower stroke mortality rates in years 10 to 25. Increases of blood pressure starting from high usual levels were associated with increased rates of stroke mortality. Systolic blood pressure was associated with stroke mortality at given levels of diastolic pressure, but diastolic blood pressure was not predictive of stroke mortality at given levels of systolic blood pressure. CONCLUSIONS Associations of systolic and diastolic blood pressure with stroke mortality were similar in cultures with different stroke mortality rates. Increases in blood pressure were associated with subsequent excess stroke mortality only in those who started from high usual levels; this study finds lower stroke risk in those men whose blood pressure increased moderately from low usual levels. Diastolic blood pressure is not independently associated with stroke risk in these populations.

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.

The role of a baseline casual blood pressure measurement and of blood pressure changes in middle age in prediction of cardiovascular and all-cause mortality occurring late in life: a cross-cultural comparison among the European cohorts of the Seven Countries Study.

Objective The first objective was to study the long-term association of a casual measurement of systolic blood pressure (SBP) with cardiovascular deaths (CVD) and all causes of death (ALL) occurring during 35 years of follow-up in different population samples of men aged 40–59 years in five European countries. The second objective was to study the predictive power of early change in SBP levels (years 0–10) in relation to late fatal events (years 10–35). Design, setting and participants A single measurement of SBP was considered in cohorts in Finland, The Netherlands, Italy, Serbia and Greece for a total of 6507 men. Three partitioned proportional hazards models were solved, one for each independent and subsequent time block of 10 years, after excluding data from the first 5 years, to predict the risk of cardiovascular disease deaths of atherosclerotic origin (CVD) and all cause mortality (ALL). Independently, the predictive power of SBP changes (Δ-SBP) occurred during the first 10 years of follow-up was explored as a possible additional risk factor in relation to CVD and ALL deaths occurring between year 10 and year 35 of follow-up. Results Partitioned hazard scores derived from the three partitioned functions were cumulated. The resulting curves showed a continuous and significant association of baseline SBP with CVD and ALL deaths during three decades, although the strength of association declined significantly from the first to the third decade. The relative risk for 20 mmHg of SBP (and its 95% confidence intervals) in predicting CVD deaths was 1.65 (1.54–1.77) for the first 10-year block; 1.33 (1.24–1.42) for the second block; and 1.22 (1.13–1.31) for the last 10-year block. The corresponding levels of ALL deaths were 1.41 (1.34–1.49), 1.26 (1.19–1.32) and 1.11 (1.05–1.17). Changes in SBP during 10 years (Δ-SBP) added predictive power to baseline measurements in a direct and significant way, with a relative risk for a change of 10 mmHg of 1.14 (1.10–1.17) for CVD deaths and 1.11 (1.09–1.13) for ALL deaths. Conclusion A single measurement of systolic blood pressure in middle-aged men maintains a strong relationship with fatal CVD and ALL deaths during the next 35 years, although for late events the strength of the association definitely declines. Changes in systolic blood pressure levels during the first 10 years of follow-up add predictive power, while baseline measurements retain their predictive power.

IX. The Greek Islands of Crete and Corfu

T HE IMMEDIATE forerunners to the present International Cooperative Study on Cardiovascular Epidemiology were two full-dress trials in September-November, 1957: one at Nicotera, a farming village close to the toe of the Italian boot, the other in a series of 11 villages in the north central part of the island of Crete. Those trials tested the proposed plans for the long-range study-the protocol, the goal of enrolling in the cohorts substantially all men of designated age in geographically defined areas, the use of international teams of examiners, chemical analyses, as well as analyses of the ECG, examination findings, etc., and statistical work to be done at the coordination center at Minnesota. Those trials fulfilled all requirements, and the experience on the island of Crete was notable in the favorable response of more than 95% of the men invited to the examinations, the willingness of the wives to participate in detailed dietary studies, the confirmation of expectations about the dominant place of olive oil in the diet, and the remarkable rarity of coronary heart disease (CHD). Financial restrictions limited the details of

Changing prevalence of coronary heart disease risk factors and cardiovascular diseases in men of a rural area of Crete from 1960 to 1991

This study compares the prevalence of coronary heart disease (CHD), risk factors (RF), and cardiovascular diseases (CVD) among Cretan men from a rural area examined in 1960 and 1991. The study population consisted of 148 men in 1960 and 42 men in 1991 of the same age group (fifty-five to fifty-nine years old) and from the same rural area. All men had a complete examination of the cardiovascular system and a resting electrocardiogram (ECG). Systolic BP (SBP) ≥140 mmHg was found in 42.6% of the subjects in 1960 and in 45.2% in 1991 (NS). Diastolic BP ≥ 95 mmHg was found in 14.9% of the subjects in 1960 as opposed to 33.3% in 1991 (P < 0.02). Total serum cholesterol (TSCH) ≥ 260 mg/dL ~6.7 mmol/L) was found in 12.8% of the subjects in 1960 and in 28.6% in 1991 (P < 0.01). Heavy smokers (≥ 20 cigarettes/daily) were 27.0% in 1960 as compared with 35.7% in 1991 (P:NS); 5.4% of the subjects in 1960 had light physical activity (PA) as compared with 14.3% in 1991 (P < 0.01); 74.7% of the subjects were farmers in 1960 as compared with 43.6% in 1991 (P < 0.1). The prevalence of CHD was 0.7% in 1960 as compared with 9.5% in 1991 (P < 0.001). Hypertensive heart disase was found in 3.4% of the subjects in 1960 and 4.8% in 1991 (NS). The prevalence of all major CVD was much higher in 1991 (19.1%) as compared with 1960 (8.8%) (P < 0.01). In conclusion, the prevalence of CHD RF and CVD was much higher in 1991 than in 1960 for Cretan men of the same age group. This higher prevalence seems to be related to dietary and life-style changes that have taken place in Crete during the last thirty years.