High R wave as a risk factor for cardivoascular and all-cause mortality. A 45-year follow-up of 13 cohorts of the Seven Countries Study.

OBJECTIVES: To study the role of high R waves predicting cardiovascular (CVD) and all-cause mortality in a male middle-aged population followed-up 45 years. MATERIAL AND METHODS: A total of 7985 CVD-free men aged 40-59 years were enrolled in 13 cohorts in seven countries (USA, Finland, the Netherlands, Italy, Serbia, Greece, Japan) and high R waves were classified by Minnesota Code 3.1 (as a dichotomous variable) from baseline resting otherwise normal ECG at entry examination together with other personal characteristics. Cox models were solved to detect the possible predictive role of high R waves for CVD and all-cause mortality. RESULTS: In Cox models high R waves were predictive of 45-year major CVD deaths with a hazard ratio of 1.17 (95% confidence intervals of 1.03-1.33) after adjustment for 6 major CVD risk factors (age, systolic blood pressure, serum cholesterol, cigarette smoking, physical activity and body mass index). The predictive role of high R wave was less evident for 45-year all-cause mortality and after adjustment for the 6 covariates the HR of high R wave lost its significance. A multiple logistic model indicated that body mass index, serum cholesterol, systolic blood pressure and mainly vigorous physical activity were directly related to high R wave prevalence while heart rate, subscapular skinfold, laterality index and shoulder pelvis shape did so in an inverse way. CONCLUSION: High R waves seem associated with an excess CVD mortality in a 45-year follow-up of middle-aged men, while their role is diluted when the end-point is all-cause mortality.

Mediterranean Diet and cardiovascular health: an historical perspective.

The first investigation of dietary intake in the Mediterranean region was undertaken at the initiative of the government of Greece in 1948. Plant foods (cereals, pulses, nuts, potatoes, vegetables and fruits) accounted for 61 % of total energy intake (TEI), animal foods (meat, eggs, fish and dairy products) for 7 % of TEI and olive oil was the main oil used. In 1950s, Ancel Keys undertook studies in USA, Italy, Spain, England, Japan, Australia and Canada leading him to hypothesise that a link could exist between diet, plasma cholesterol and CHD. Between 1958 and 1964, Keys and co-workers carried out the Seven Countries Study, which enrolled men aged 40-59 years in one of sixteen cohorts from seven countries (Finland, Greece, Italy, Yugoslavia, Japan, USA and Italy). After 15-, 25- and 50-year follow-up, a strong positive relation was observed between saturated fat intake and CHD mortality, and a negative one with Mediterranean Dietary Index. In 1975, Keys and his wife published a book entitled: 'How to eat well and stay well. The Mediterranean way', which popularised Mediterranean Diet (MedDiet). After 45-year follow-up, longevity without CHD death was 12·9 years higher in Crete than in Finland. Protecting effect of MedDiet towards CHD incidence and risk is now confirmed by Prevencion con Dieta Mediterranea study and by cohorts' studies gathered in several recent meta-analyses. MedDiet is sustainable and recognised by UNESCO as an intangible cultural heritage, which is the most beautiful homage that can be paid to Ancel Keys and all his co-workers.

Ancel Keys: The legacy of a giant in physiology, nutrition, and public health.

Ancel Keys, whose life spanned over 100 years (1904-2004), made a wealth of seminal scientific and public health contributions. As a physiologist, nutritionist, and public health scientist, he has left his mark on the 20th century by exploring different areas of physiology and nutrition, as well as by contributing to the understanding of basic public health issues. Among his major achievements one can mention in chronological order: studying adaptation to very high altitude, developing the K ration to enable the US military to survive with light but dense food, dissecting the physiology of starvation and nutritional rehabilitation to optimize recovery of functions, uncovering the link between serum cholesterol and heart disease, coordinating the first multi-country epidemiological longitudinal study in nutrition and health, coining the word "body mass index" (BMI), which he showed to be the best body weight index to predict body fat, and promoting the Mediterranean diet for a healthy life style. This review examines the historical events and scientific intrigues that have surrounded Ancel Keys's major classical studies that have ensured him a central place in the history of medical science.

How the Seven Countries Study contributed to the launch and development of cardiovascular epidemiology in Italy. A historical perspective.

The Italian research group of the Seven Countries Study of Cardiovascular Diseases (SCS), through the independent use of the national cohorts and data, had the lucky opportunity, starting in the early 1960, to launch the Italian research in epidemiology of cardiovascular diseases (CVD). In this way, the Italian Section of that international study became the first investigation with baseline measurements in various cohorts, subsequent re-examinations, systematic search for morbid events, and follow-up for mortality up to 50 years. A large number of scientific aspects has been tackled including estimates of morbidity and mortality rates, the association of risk factors with cardiovascular events and total mortality, the role of risk factor changes, the use of multivariable models, the role of lifestyle behavior, the determinants of all-cause mortality including risk factors rarely measured in other studies, the identification of characteristics of a condition called Heart Disease of Uncertain Etiology (HDUE), the production of predictive tools for practical use and several other issues. All this has been enhanced by the availability of extremely long follow-up data rarely found in other studies. Field work organization, measurement techniques, diagnostic criteria, data handling and computing had the limitations and difficulties typical of those times, the mid of last century, when CVD epidemiology was at its beginning. All this represented anyhow the start of CVD epidemiology research in the country and was the stimulus to the start of other studies and a valuable collaboration with some of them.

Landmark studies in coronary heart disease epidemiology. The Framingham Heart Study after 70 years and the Seven Countries Study after 60 years.

This year we celebrate anniversaries of two prospective studies that have contributed most to our understanding of the epi-demiology of coronary heart disease (CHD): the Framingham Heart Study (FHS) and the Seven Countries Study (SCS). The FHS was initiated 70 years ago and is continued in the subsequent generations using new research opportunities, including evaluation of the risk factors for chronic non-cardiovascular diseases. The SCS is now finished because the original study population are mostly deceased, and the study did not continue in the children and grandchildren of the participants. The FHS allowed identification of factors predisposing to CHD, which were referred to as "risk factors" for the first time. Based on the FHS findings, a multivariate model of the 10-year CHD risk was developed, known as the Framingham Heart Score. In addition, criteria of heart failure and risk factors for atrial fibrillation were defined. The SCS provided the first evidence for an association between nutrition and CHD and laid the foundations for recommending the Mediterranean diet for cardio-vascular disease prevention.

Age at death of major cardiovascular diseases in 13 cohorts. The seven countries study of cardiovascular diseases 45-year follow-up.

OBJECTIVES: To explore age at death (AD) for major cardiovascular diseases (CVD) and their risk factors in originally middle-aged men followed nearly to extinction in the Seven Countries Study. MATERIALS AND METHODS: Thirteen cohorts of men aged 40-59 years (N = 10,628) in seven countries (USA, Finland, the Netherlands, Italy, Serbia, Greece, Japan) were enrolled in late 1950s and early 1960s and were followed 45 years for mortality. AD was computed for coronary heart disease (CHD), stroke (STR), heart disease of uncertain aetiology (HDUE) and for all-causes. AD was compared across CHD-HDUE-STR. Cox models were computed for each end-point using baseline age, cigarettes smoking, systolic blood pressure and serum cholesterol. RESULTS: After 45 years 92.9% of men had died. The most common CVD death was CHD in most cohorts except some Mediterranean and Japanese cohorts where STR or HDUE were most prevalent. In 13 cohorts mean AD was 74.5, 73.5, 75.7 and 79.1 years, respectively, for all-cause, CHD, STR and HDUE mortality (all possible differences were significant). The difference, across cohorts, between the highest and the lowest mean AD was 12.9, 9.0 and 4.7 years for CHD, HDUE and STR mortality, respectively. Risk factors explored were significant predictors of all three CVD end-points, except serum cholesterol, specific to CHD mortality. CONCLUSIONS: AD is a useful indicator of previous health and aging populations. STR and HDUE are diseases appearing later in life, thus being associated with a higher AD compared with CHD mortality.

Baseline fatty acids, food groups, a diet score and 50-year all-cause mortality rates. An ecological analysis of the Seven Countries Study.

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.

Invited Commentary: 30-Year Perspective on the Seven Countries Study.

In a 1986 article (Am J Epidemiol. 1986;124(6):903-915), Keys et al. described and discussed 15-year findings from 15 cohorts of the Seven Countries Study (SCS), the first systematic study of diet, risk characteristics, disease-specific death rates, and their ecologic and individual associations both among and within whole populations of working men in regions with contrasting traditional diets. The SCS findings included 30-fold cohort differences in rates of death from coronary heart disease and 3-fold differences in rates of death from all causes, along with strong ecologic associations among diet, risk factors, and disease rates. These results have motivated a generation of causal research conducted using bench, clinical, and population strategies. The study has contributed to survey methods, preventive practice, nutrition science, and policy on health, food and agriculture, and diet. The article is a succinct and accessible account by Ancel Keys, near the end of his long career, of the SCS design, conduct, and findings, with his discussion and interpretation of their importance. My commentary deals with the extent, validity, and historical meaning of SCS findings, as well as their influence and the influence of the 1986 article itself on epidemiologic thought and on public health. Students of epidemiology and of history should read this rich original source.

Seven Countries Study cohort in Crete, Greece: gluteal adipose-tissue fatty-acid profiles of survivors, at 2010.

OBJECTIVE: To analyse the gluteal adipose-tissue fatty-acid profiles from Cretan cohort survivors of the Seven Countries Study (SCS) at 2010 and to compare them with those of survivors assessed in 2000, as well as with literature data on male Cretans at 1965. DESIGN: We analysed data concerning the gluteal adipose-tissue fatty acids (analysed by GC) from three studies. SETTING: The island of Crete (rural areas and the city of Heraklion). SUBJECTS: Twenty-two of the 2010 SCS survivors aged 90 years and over; seventy-eight men aged 80 years of the 2000 SCS survivors; and 280 men assessed in 1965. RESULTS: In comparison to 1965 and 2000, the SCS survivors in 2010 had a higher amount of 18:1n-9 (P<0·05) in their gluteal adipose tissue and a lower amount of PUFA (P<0·05). On the other hand, a constant decrease in adipose-tissue 14:1n-5 and 16:1n-7 was recorded between 1965 and 2010 (P<0·001), and between 2000 and 2010 (P<0·05), while 18:2n-6 appeared to decrease between the 1965 and 2010 assessments (P<0·001). CONCLUSIONS: Comparison with a 1965 representative Cretan sample and 2000 SCS survivors indicated an increased concentration of oleic acid (known for its protective role against mortality) and a decreased concentration of PUFA (known for their susceptibility to oxidation) in our surviving sample at 2010. These changes may reflect internal physiological processes due to diet change within these years and/or ageing.

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.

Validity of the cohort of Crete in the Seven Countries Study: A time-series study applied to the cancer mortality trend between 1960 and 2011.

We examined whether the Cretan cohort of the Seven Countries Study (SCS) is representative for the entire population in the island using cancer mortality registries. The analysis was carried out on the Cretan cohort of the SCS cancer mortality data and a similar cancer registry for the general population during a 51-year follow-up (1960-2011). Information about the causes of mortality was obtained from official death certificates and classified according to the International Classification of Diseases, 9th Revision (ICD-9). Two time-series models of mortalities from cancer, using data from the Cretan cohort and the Hellenic Statistical Office (EL. STAT), were developed using Matlab software. The existence of long-term memory in the data was tested by rescaled range analysis (Hurst-Mandelbrot). State-space reconstruction was applied to identify the simplest system that was able to re-create the present time-series. In the cohort, cancer mortalities accounted for 18.9% of total mortalities. The EL.STAT time-series analysis generated mean V statistics (95%CI) of 0.69815 (0.398-0.999) and 0.677143 (0.301-0.897) for the general population and the seven countries cohort, respectively. The embedding dimension for the EL.STAT data was equal to 1 for the general population and for the Cretan cohort (m=1). The exponent H values for the two time-series were almost equal. In the two time-series the proposed time delay of cancer mortalities was 2. The Cretan cohort of the SCS and the entire population of the island followed similar patterns of cancer mortality over time.