How the Seven Countries Study contributed to the definition and development of the Mediterranean diet concept: a 50-year journey.

The Seven Countries Study of Cardiovascular Diseases was started at the end of the 1950s and it continues to be run after >50 years. It enrolled, at entry, 16 population cohorts in eight nations of seven countries for a total of 12,763 middle-aged men. It was the prototype of epidemiological studies seeking cultural contrasts and the first to compare cardiovascular disease (CVD) rates related to diet differences. The study has shown that populations suffer widely different incidence and mortality rates from coronary heart disease (CHD) as well as from other CVDs and overall mortality. Higher rates were found in North America and northern Europe, and lower rates in southern Europe - Mediterranean countries - and Japan. These differences in CHD rates were strongly associated with different levels of saturated fat consumption and average serum cholesterol levels, with lowest rates in Greece and Japan where the total fat intake was very different. The cohorts were also different in dietary patterns defined by the ratio of calories derived from plant foods and fish on the one hand and calories derived from animal foods and sugar on the other. These findings pointed to the so-called Mediterranean diet, which is characterized by large values of that plant/animal ratio, a pattern associated with lower incidence and mortality from CHD and also with the lowest death rates and the greatest survival rates. More recent studies have refined these concepts and documented on a larger scale the virtues of these eating habits.

The association of the Mediterranean Adequacy Index with fatal coronary events in an Italian middle-aged male population followed for 40 years.

BACKGROUND AND AIMS: The dietary habits defined as the Mediterranean diet have shown to be protective for coronary heart disease (CHD) and other morbid conditions. The present analysis aims to test the Mediterranean Adequacy Index (MAI), a dietary index derived from the Mediterranean habits, versus the occurrence of fatal CHD events in an Italian male population followed for 40 years. METHODS AND RESULTS: In 1965, at the time of the 5-year follow-up examination of the Italian Rural Areas of the Seven Countries Study, the diet was assessed by the dietary-history method in 1139 men aged 45-64 years, free from previous coronary events, in the rural communities of Crevalcore (Northern Italy) and Montegiorgio (Central Italy). MAI has been computed and its natural log (lnMAI) used for the analysis. Mortality data were collected and coded for the subsequent 40 years. The lnMAI was inversely associated with CHD mortality at 20 and 40 years when entered alone in the Cox proportional hazards model and when adjusted for age, cigarette smoking, systolic blood pressure, serum cholesterol, physical activity and body mass index. The hazard ratio for 1 unit of lnMAI (roughly corresponding to 2.7 units of MAI) was associated with a CHD mortality reduction of 26% in 20 years and 21% in 40 years of follow-up, when adjusted for the covariates. CONCLUSIONS: In an Italian middle-aged male population, MAI showed the protective effect of a healthy Mediterranean Diet pattern versus the occurrence of fatal CHD events at 20 and 40 years.

The role of HDL cholesterol in metabolic syndrome predicting cardiovascular events. The Gubbio population study.

BACKGROUND AND AIMS: Metabolic syndrome (MS) has recently been claimed to be an important new risk factor for the occurrence of coronary heart disease (CHD) and cardiovascular disease (CVD) events, although it is simply a combination of known risk factors used in a dichotomized fashion. The aims of this analysis were to explore the predictive role of MS for CHD and CVD events in a population study, in comparison with using the same factors in a continuous fashion, with special emphasis on HDL cholesterol. METHODS AND RESULTS: In the second examination of the Gubbio population study from central Italy, 2650 cardiovascular disease-free men and women, aged 35-74 years around 1990, were examined and followed-up for 12 years. The classic risk factors (sex, age, systolic blood pressure, serum cholesterol and smoking habits) were studied as predictors of CHD and CVD events, alone and with the contribution of other factors (HDL cholesterol, blood glucose, serum triglycerides and waist circumference) included in the so-called MS, based on several multivariate models. MS was also tested after adjustment for other risk factors. MS produced a predictive significant relative risk of 1.67 for CHD events and 1.82 for CVD events, but considering its single risk factors, the only ones contributing to prediction were HDL cholesterol and systolic blood pressure. Dedicated analyses showed that MS does not add anything to the power of prediction beyond the role of the single risk factors treated in a continuous fashion, while the best predictive power is obtained using classic risk factors (sex, age, smoking habits, total cholesterol, systolic blood pressure) with the addition of HDL cholesterol. CONCLUSIONS: The predictive power of MS is bound only to the presence of HDL cholesterol and blood pressure and does not add anything to using the same risk factor treated in a continuous fashion.

Chromosome painting shows that skunks (Mephitidae, Carnivora) have highly rearranged karyotypes.

The karyotypic relationships of skunks (Mephitidae) with other major clades of carnivores are not yet established. Here, multi-directional chromosome painting was used to reveal the karyological relationships among skunks and between Mephitidae (skunks) and Procyonidae (raccoons). Representative species from three genera of Mephitidae (Mephitis mephitis, 2n = 50; Mephitis macroura, 2n = 50; Conepatus leuconotus, 2n = 46; Spilogale gracilis, 2n = 60) and one species of Procyonidae (Procyon lotor, 2n = 38) were studied. Chromosomal homology was mapped by hybridization of five sets of whole-chromosome paints derived from stone marten (Martes foina, 2n = 38), cat, skunks (M. mephitis; M. macroura) and human. The karyotype of the raccoon is highly conserved and identical to the hypothetical ancestral musteloid karyotype, suggesting that procyonids have a particular importance for establishing the karyological evolution within the caniforms. Ten fission events and five fusion events are necessary to generate the ancestral skunk karyotype from the ancestral carnivore karyotype. Our results show that Mephitidae joins Canidae and Ursidae as the third family of carnivores that are characterized by a high rate of karyotype evolution. Shared derived chromosomal fusion of stone marten chromosomes 6 and 14 phylogenetically links the American hog-nosed skunk and eastern spotted skunk.

Cigarette smoking and mortality risk: twenty-five-year follow-up of the Seven Countries Study.

BACKGROUND: Although most observations in the Seven Countries Study suggest that cigarette smoking is harmful for health, universality of this conclusion remains controversial. SUBJECTS AND METHODS: Cohort-specific and pooled smoking habits at baseline (1957-1964) in 12 763 men aged 40 through 59 years living in Europe, the United States, and Japan in relation to 25-year mortality follow-up. Pooled hazard ratios for smokers vs never smokers were calculated by the Cox proportional hazards model, adjusting for baseline country of residence, age, body mass index, serum cholesterol, systolic blood pressure, and clinical cardiovascular disease. RESULTS: Adjusted hazard ratios for all-causes death in smokers compared with never smokers were 1.3 (95% confidence interval, 1.2-1.4) for smokers of less than 10 cigarettes per day and 1.8 (95% confidence interval, 1.7-1.9) for smokers of 10 cigarettes per day or more. Hazard ratios were elevated for death due to coronary heart disease, all stroke, other arterial disease, lung cancer, other cancer, chronic obstructive pulmonary disease, and other disease in smokers compared with never smokers. Within country, a few instances in which never smokers had a higher cause-specific death rate than smokers of 10 cigarettes per day or more were attributable to random variation associated with low prevalence of never smokers and multiple comparisons. CONCLUSIONS: These findings confirm the association of cigarette smoking with elevated risk of mortality from all causes, several cardiovascular diseases, cancer, and chronic obstructive pulmonary disease. Risk associated with cigarette smoking is independent of culture.

Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study.

OBJECTIVE: To determine whether flavonoid intake explains differences in mortality rates from chronic diseases between populations. DESIGN: Cross-cultural correlation study. SETTING/PARTICIPANTS: Sixteen cohorts of the Seven Countries Study in whom flavonoid intake at baseline around 1960 was estimated by flavonoid analysis of equivalent food composites that represented the average diet in the cohorts. MAIN OUTCOME MEASURES: Mortality from coronary heart disease, cancer (various sites), and all causes in the 16 cohorts after 25 years of follow-up. RESULTS: Average intake of antioxidant flavonoids was inversely associated with mortality from coronary heart disease and explained about 25% of the variance in coronary heart disease rates in the 16 cohorts. In multivariate analysis, intake of saturated fat (73%; P = 0.0001), flavonoid intake (8%, P = .01), and percentage of smokers per cohort (9%; P = .03) explained together, independent of intake of alcohol and antioxidant vitamins, 90% of the variance in coronary heart disease rates. Flavonoid intake was not independently associated with mortality from other causes. CONCLUSIONS: Average flavonoid intake may partly contribute to differences in coronary heart disease mortality across populations, but it does not seem to be an important determinant of cancer mortality.

Diet and 20-y mortality in two rural population groups of middle-aged men in Italy.

The relationships between individual diet, measured in 1965 on the two Italian rural cohorts of the Seven Countries Study on Cardiovascular Disease, and subsequent mortality from all and specific causes of death in 20 y are studied. The analysis covers 1536 men aged 45-64 y at entry to the study. By using a cluster analysis technique, individuals are aggregated into four groups so that the elements within a group have a higher degree of similarity in dietary nutrients than between groups. Impressive differences in death rates between groups are found especially at the 10- and 15-y anniversaries. The relative risk between the least and the most favored group in 15-y mortality from coronary heart disease is 4.7; in 10 y the relative risk for cancer mortality is 2.9 and for liver cirrhosis approximately 4.

Food consumption patterns in the 1960s in seven countries.

At the end of the 1950s the Seven Countries Study was designed to investigate the relations between diet and cardiovascular diseases. Sixteen cohorts were selected in Finland, Greece, Italy, Japan, The Netherlands, United States, and Yugoslavia. During the 1960s food consumption data were collected from random samples of these cohorts by use of the record method. In Finland the intake of milk, potatoes, edible fats, and sugar products was very high. A similar but lower intake pattern was observed in The Netherlands. Fruit, meat, and pastry consumption was high in the United States; cereal and alcoholic drink consumption was high in Italy; and bread consumption high in Yugoslavians except for those in Belgrade. In Greece the intake of olive oil and fruit was high and the Japanese cohorts were characterized by a high consumption of fish, rice, and soy products. These differences in food consumption patterns have lessened during the past 25 y.

Markers of insulin resistance and colorectal cancer mortality.

A link between insulin metabolism and colorectal cancer has been hypothesized, supported by a series of potential physiological mechanisms, and confirmed by a number of reports in experimental animals. However, the evidence in humans is limited and mostly indirect. The aim of the present report is to analyze whether individuals with a cluster of metabolic abnormalities associated with abnormalities in insulin metabolism experience higher mortality for colorectal cancer than those without this cluster of metabolic abnormalities. A total of 21,311 men and 15,991 women 20-69 years of age were followed-up for an average of 7 years as part of the Risk Factors and Life Expectancy Project, a pooling of a number of epidemiological studies conducted in Italy. Our analyses indicate that participants with high levels of blood glucose and a cluster of metabolic abnormalities linked to insulin resistance experienced a significant increased risk of colorectal cancer mortality compared with participants without the cluster. For the presence of the cluster of metabolic abnormalities, the calculated hazard ratios and 95% CIs were 2.96 (1.05-8.31) for men, 2.71 (0.59-12.50) for women, and 2.99 (1.27-7.01) when both sexes were combined. These associations were independent from the potential confounding effect of age, drinking of alcoholic beverages, and smoking. Our findings are supportive of the hypotheses that glucose metabolism hyperinsulinemia, insulin resistance, and metabolic abnormalities associated with it may play a significant role in the etiology of colorectal cancer.

Blood lipids in Italy. Regional differences.

Serum cholesterol and triglyceride levels have been evaluated in samples from fasting males aged 20--59 in Northern (Brisighella), Central (Rome) and Southern (Pozzuoli) Italy. Regularly performed quality controls between laboratories assured comparability of data. A statisitically significant difference of mean serum cholesterol and triglyceride levels was observed for most age-groups in the 3 different areas, lower values being found in the southern population as compared to the central and northern ones. These results support previous findings and the thesis that large differences in blood lipid levels may still exist even within the same country and that they at least in part may be culturally determined in connection with different dietary habits.

The predictive role of systolic, diastolic and mean blood pressures on cardiovascular and all causes of death.

Systolic (SBP), diastolic (DBP) and mean [MBP = diastolic + 1/3 (systolic - diastolic)] blood pressures were compared as predictors of all causes of death (ALL) and of deaths from atherosclerotic cardiovascular disease (ACVD) in 2480 men, aged 40-59 years, belonging to three cohorts followed up for 20 years. Both univariate analysis, based on distribution of events in age-specific quintile classes of blood pressures, and multivariate analysis, based on the Cox proportional hazards model with five covariates as possible confounders, clearly showed the superiority of SBP over DBP in predicting fatal events; MBP played an intermediate role.

Impact of the Gubbio population study on community control of blood pressure and hypertension. Gubbio Study Research Group.

BACKGROUND: Awareness and treatment of hypertension have markedly increased in the last 30 years in most parts of the world, but a satisfactory control of blood pressure is still infrequent OBJECTIVES: To describe trends in community control of hypertension and blood pressure levels in the small town of Gubbio, Italy. METHODS: Large samples of the populations (aged 30-79 years) were examined 6 years apart for measurement of blood pressure, other cardiovascular risk factors and knowledge, attitude and practice towards control of hypertension. Data were available from a total of 1125 men and 1445 women with two examinations and 1566 men and 1658 women with at least one examination. Two different definitions of hypertension were used (old definition: systolic blood pressure (SBP) > or = 160 mmHg or diastolic blood pressure (DBP) > or = 95 mmHg or use of antihypertensive drugs; recent definition: SBP > or = 140 mmHg or DBP > or =90 mmHg or use of anti-hypertensive drugs). RESULTS: Awareness, treatment and control of hypertension increased from one survey to the other, whatever definition of hypertension was used. Control rose from 41 to 63% (old definition) and from 12 to 24% (recent definition). In a 6-year period, the average population SBP declined 2-8 mmHg and DBP declined 2-3 mmHg depending on type of analysis, against an expected rise of 9 mmHg for SBP and 2 mmHg for DBP. These trends are partly explained by a marked decline in alcohol consumption and by more common and intensive anti-hypertensive treatment, while change in body mass index, which showed a slight but systematic increase, cannot be considered as a contributor to this trend. CONCLUSIONS: An epidemiological study has motivated a population group and its medical profession towards a better control of hypertension.

Haemostatic parameters and lifestyle factors in elderly men in Italy and The Netherlands.

The association between plasma fibrinogen, factor VII, factor X, activated partial thromboplastin time, antithrombin III and the lifestyle factors cigarette smoking, alcohol use, fat intake and physical activity was assessed in 802 men aged 70-90 years in Zutphen (The Netherlands), Montegiorgio and Crevalcore (Italy). Smoking was positively associated with fibrinogen, also after adjustment for other lifestyle factors, age, use of anticoagulants and aspirin like drugs, body mass index, and history of myocardial infarction. Alcohol use was associated with increased levels of factor X and decreased levels of antithrombin III. Fat intake was positively associated with antithrombin III. Between cohorts, considerable differences were observed in levels of haemostatic parameters and the lifestyle factors. Compared to the mediterranean cohorts the Zutphen cohort showed the highest levels of fibrinogen and factor VII. Differences in lifestyle factors could, however, not explain differences between cohorts in levels of any of the haemostatic parameters, despite the observed associations between lifestyle factors and haemostatic parameters.

Serum triglycerides in the prediction of coronary artery disease (an Italian experience).

An occupational group living in Rome and composed of 3,007 men aged 46 to 65 years who were free from previous major coronary events was screened for a number of coronary risk factors and then followed up for 10 years. In all, 107 coronary deaths occurred in 10 years. There was a positive relation between coronary death rate and increasing levels of triglycerides, but the difference between the extreme quintile classes was not any more significant after adjustment for cholesterol levels. A cross-classification involving low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels showed a higher coronary artery disease (CAD) mortality in subjects with a higher LDL cholesterol/HDL cholesterol ratio and higher triglycerides. However, the excess risk in this subgroup was largely explained by the mean levels of total cholesterol. The multivariate proportional-hazards Cox model with coronary deaths as the end point, and age and triglycerides as predictors, produced a significant coefficient for triglycerides that became nonsignificant when other lipids alone or in combination (total, HDL and LDL cholesterol and some of their ratio) were fed into the model as further covariates. It is concluded that there is no evidence of an independent role of triglycerides in the prediction of coronary deaths.

Voltage criteria of left ventricular hypertrophy in sudden and nonsudden coronary artery disease mortality: the Italian section of the Seven Countries Study.

It is unclear whether sudden or nonsudden death can be predicted independently from other risk factors for coronary artery disease (CAD). Therefore, this investigation was undertaken to measure 12-lead QRS voltage sum, a recently proposed (Am J Cardiol 1985;55:485-494) index of left ventricular (LV) hypertrophy, and its ability to predict either subsequent sudden (less than 2 hours) or nonsudden CAD death during 20 to 23 years of follow-up in 1,588 middle aged men (40 to 61 years old) from 2 cohorts of the Italian section of the Seven Countries Study who were free of demonstrable CAD (at entry examination in 1962). The Sokolow-Lyon and the modified Sokolow-Lyon indexes, 2 standard electrocardiographic methods to detect LV hypertrophy were also measured and compared. During follow-up, 67 patients died suddenly and 87 died a nonsudden CAD death. In the Cox proportional-hazards model, age, mean blood pressure, heart rate, body mass index, cholesterol, physical activity, smoking habit, ST-T alterations (Minnesota codes 4.1 to 4.3 together with 5.1 to 5.3) and the 3 electrocardiographic indexes, all measured at the time of enrollment into the study, were included. The 12-lead QRS voltage sum retained significant and independent relation to sudden death (t = 2.00); Sokolow-Lyon index entered the Cox solution for nonsudden CAD death but the association was inverse (t = -2.10). ST-T alterations were significantly associated only with nonsudden CAD death (t = 2.19). Thus, in addition to several known risk factors, measurement of 12-lead QRS voltage sum in middle-aged men without clinical evidence of heart disease may help identify subjects at an increased risk of sudden death; nonsudden CAD death is predicted by Sokolow-Lyon index and by ST-T alterations. The usefulness of these indexes needs to be tested in different populations.

Epidemiology of silent myocardial ischemia in asymptomatic middle-aged men (the ECCIS Project).

To evaluate the prevalence of type I silent myocardial ischemia and silent myocardial infarction, 4,842 men aged 40 to 59 years, identified in occupational samples in Florence and Rome, and free from major heart disease, severe illnesses and chest pain, underwent a 3-stage diagnostic procedure. The first stage included resting electrocardiogram, hyperventilation test, exercise electrocardiogram and 24-hour Holter electrocardiogram. The subjects who were suspected of having type 1 silent myocardial ischemia or previous silent infarction at the first stage (n = 439; 9.1%) were entered into the second stage, which included echocardiogram, thallium 201 scintigraphy in conjunction with exercise testing or dipyridamole test, exercise radionuclide ventriculography and ergonovine test. Three hundred eighty-seven men participated in the second stage; after the diagnostic procedures were performed, 104 men (2.1%) were still suspected of having type 1 silent myocardial ischemia or infarction on the basis of predefined criteria. Sixty-two men continued on into the third diagnostic workup including coronary angiography. The final diagnosis of type 1 silent myocardial ischemia or infarction was reached in 25 patients (prevalence 0.52%; adjusted estimate 0.89%). Of these 25, 19 had coronary atherosclerotic disease, 1 had Kawasaki disease, 1 had coronary anomaly, 1 had induced focal coronary spasm, and 2 had normal coronary arteriograms despite the presence of unquestionable old myocardial infarction. Altogether, 6 patients with silent myocardial infarction were identified.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship of total serum cholesterol to coronary heart disease in older men. The Italian rural areas of the Seven Countries Study.

The relationship of serum cholesterol to the development of major coronary events (CHD) was studied in Italian rural cohorts of adult men aged 40-59 (n = 1672) and of older men aged 65-79 (n = 752) followed up for 5 years. In adult men both univariate and multivariate analysis (the latter with 4 or 5 covariates fed into the Cox model) showed a direct and significant relationship of cholesterol to CHD. In older men the univariate analysis confirmed a direct and significant relationship; for the multivariate analysis none of the considered factors was significantly predictive.

Alcohol and blood pressure. The effects of age. Findings from the Italian Nine Communities Study. The Research Group ATS-RF2 of the Italian National Research Council.

This report analyzes the role age in the association between alcohol consumption and blood pressure in a large sample (n = 6165) of Italian men and women, aged 20 to 59 years, who participated in a multicenter study on risk factors for arteriosclerosis. Age-stratified analysis indicated that both men and women aged 50 to 59 years showed the strongest positive association between alcohol consumption and blood pressure. While in men the association between systolic blood pressure and alcohol consumption increased linearly with age, in women the association between systolic blood pressure and alcohol increased sharply in the oldest (50 to 59 year) age group.

Association of blood lead to blood pressure in men aged 55 to 75 years: effect of selected social and biochemical confounders. NFR Study Group.

The association of blood lead (B-Pb) concentration to blood pressure was investigated in men aged 55 to 75 years living in the Rome area, who had no history of exposure to lead in the workplace and who participated between 1989 and 1990 in an epidemiologic survey for coronary heart disease (New Risk Factor Project). Of the 1856 individuals eligible for the study, 59 were excluded from analyses because not all relevant data were available; and 478 were excluded because they were treated for hypertension. In the remaining subjects (n = 1319) the median B-Pb concentration was 113 micrograms/l (range: 40-442 micrograms/l). Systolic blood pressure (SBP) averaged 140 +/- 18 (standard deviation) mm Hg (range 98-220) and diastolic blood pressure (DBP) 84 +/- 9 mm Hg (range 56-118). Median B-Pb values increased significantly from 111 micrograms/l in subjects with normal blood pressure (n = 668) to 113.5 micrograms/l in subjects with borderline high blood pressure (n = 373) and to 120 micrograms/l in subjects with increased blood pressure (n = 278). After log-normal conversion of B-Pb, the linear correlation coefficient between In[B-Pb(ug/l)] and both SBP and DBP was statistically significant (r = 0.1332, p < 0.001 and r = 0.0737, p = 0.007, respectively). The linear regression coefficient was 6.8 mm Hg/In(micrograms/l) for SBP and 1.8 mm Hg/In(microgram/l) for DBP. Multiple regression analyses revealed that, after correction for body mass index (BMI), age, heart rate, skinfold thickness, serum lipids, and glucose levels; blood lead was still a significant predictor of increased SBP and DBP.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence of morbidity and multimorbidity in elderly male populations and their impact on 10-year all-cause mortality: The FINE study (Finland, Italy, Netherlands, Elderly).

Older males are known to carry, more likely than younger people, one or more chronic diseases with an expected impact on mortality. This study was aimed at identifying the relationship of prevalent chronic diseases in elderly populations of different countries with all-cause mortality. Men aged 65-84 from defined areas were enrolled in Finland (N=716), the Netherlands (N=887) and Italy (N=682). They were survivors of cohorts studied for 25 years within the Seven Countries Study. Major chronic diseases were diagnosed at entry. Ten-year follow-up for mortality was completed. Entry prevalence of selected chronic diseases was higher in Finland (56%) than in Italy (51%) and the Netherlands (44%). Ten-year age-adjusted death rates from all causes were higher in Finland (565 per 1000) and lower in the Netherlands (478 per 1000) and Italy (445 per 1000). The absolute risk of death related to chronic disease was high in the three countries, but was higher in Finland than in the Netherlands and Italy. The most lethal condition was stroke, with 10-year death rates of 806 per 1000 in Finland and 707 and 729 per 1000 in the Netherlands and Italy, respectively. The relative risk of all-cause mortality for a set of seven chronic diseases (coronary heart disease, heart failure, claudicatio intermittens, cerebrovascular accidents, diabetes, COPD and cancer) adjusted by age, other diseases and cohort was less than two for each condition, except cerebrovascular accidents in the Netherlands (RR 2.20). In general, relative risk was higher in Finland, intermediate in the Netherlands and lower in Italy, where only cerebrovascular accidents, intermittent claudication, diabetes and the presence of any chronic condition had a significant relative risk. About one third of men had one chronic disease, and between 10% and 15% had two diseases. The coexistence of any two or three chronic conditions was associated with a relative risk of 2 or more in Finland and the Netherlands and less than 2 in Italy. In these elderly men prevalent morbidity and comorbidity was relatively common and it explained a large proportion of excess in all-cause mortality in 10 years of follow-up.