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The year 2020 celebrated the tenth anniversary of the recognition of the Mediterranean Diet as Intangible Cultural Heritage of Humanity by the UNESCO Intergovernmental Committee. This event represented a milestone in the history of nutrition, as the Mediterranean diet was the first traditional food practice to receive such award. Since then, a lot has been discussed not only on the beneficial aspects of the Mediterranean diet, but also on its complex role as a lifestyle model that includes a set of skills, knowledge and intercultural dialogue. This process ended up with the recognition in 2019 of Mediterranean diet as a possibly universal model of healthy diet from the EAT-Lancet Commission. These concepts were widely debated at the 2019 "Ancel Keys" International Seminar, held in Ascea (Italy) (for more information see: www.mediterraneandietseminar.org) with the aim to stimulate interest and awareness of a young group of participants on the current problems inherent to the effective implementation of the Mediterranean diet. The present article collects the contributions of several lecturers at the Seminar on key issues such as methodological and experimental approach, sustainability, molecular aspects in disease prevention, future exploitation, without neglecting a historical view of the Seven Countries Study. From the Seminar conclusions emerged a still vibrant and modern role of Mediterranean diet. The years to come will see national and international efforts to reduce the barriers that limit adherence to Mediterranean diet in order to plan for multi-factorial and targeted interventions that would guide our populations to a sustainable healthy living. (C) 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Background and aim The association of serum cholesterol levels with the occurrence of coronary heart disease (CHD) mortality during a follow-up of 50 years was rarely investigated previously. Thus, we took advantage of results at hand in 10 pooled cohorts of men aged 40–59 years from the Seven Countries Study (9063 individuals and 2057 CHD fatal events) and we assessed this. Methods and results Cox proportional hazards models were run with CHD fatal events (as dependent variable) and cholesterol levels (as independent variables) at years 0, 10, and 25 (in 5 cohorts). Cumulative events during subsequent decades (cumulative approach: CA) and separately in each subsequent decade (partitioned approach: PA) were analyzed. The ecological correlation of average baseline serum cholesterol levels with CHD mortality was very high (R = 0.97). Serum cholesterol and CHD mortality for 50 years were associated at the individual level, and the association estimated by the Cox's coefficients (and related hazards ratios) was initially strong in both CA and PA, but slightly declined during later decades. Hazards ratios (for a difference of 40 mg/dl) ranged from 1.39 to 1.20 for CA and from 1.39 to 0.80 for PA. Coefficients were larger for CA than for PA and the decline was more evident for the latter. Partitioned coefficient became negative and significant in the last decade (from year 40–50). Coefficients derived from cholesterol levels measured at year 10 of follow-up showed similar trends but their magnitude was smaller. Conclusion Thus, the relationship of serum cholesterol levels with CHD mortality remained relatively stable during at least 40 years after a single cholesterol measurement at baseline in middle-aged men.

We investigated the relationship between time trends in nutrient intake and coronary risk factors/mortality rates in Tanushimaru, a Japanese cohort of the Seven Countries Study. All men between the ages of 40 and 64 were enrolled. Subjects numbered 628 in 1958, 539 in 1977, 602 in 1982, 752 in 1989, 402 in 1999, 329 in 2009, and 160 in 2018. Eating patterns were evaluated by 24-h dietary recall from 1958 through 1989, and by a food frequency questionnaire administered from 1999 through 2018. The total daily energy intake decreased from 2,837 kcal in 1958 to 2,096 kcal in 2018. Carbohydrate intake as a percentage of the total decreased remarkably from 84% (1958) to 53% (2018), whereas there was a large increase in fat intake (from 5 to 24%) during the same period. Age-adjusted mean cholesterol levels rose sharply (from 167.9 to 209.4 mg/dl) and body mass index levels also increased (from 21.7 to 24.4 kg/m2), but smoking rate decreased from 69% (1958) to 30% (2018). The mortality rates from stroke and cancer declined, but mortality from myocardial infarction and sudden death remained stable at low levels. The remarkable changes in dietary patterns over the last 60 years can be related to coronary risk factors, but not currently to the mortality of coronary artery disease; more follow-up is needed.

Observational epidemiological studies provide valuable information regarding naturally occurring protective factors observed in populations with very low prevalences of vascular disease. Between 1935 and 1965, the Italian-American inhabitants of Roseto (Pennsylvania, USA) observed a traditional Italian diet and maintained half the mortality rates from myocardial infarction compared with neighboring cities. In the Seven Countries Study, during 40years (1960-2000) Crete maintained the lowest overall mortality rates and coronary heart disease fatalities, which was attributed to strict adherence to the Mediterranean diet. In the French Three-City Study, a ten-year follow-up (2000-2010) showed that higher consumption of olive oil was associated with lower risk of death, as well as protection from cognitive decline and stroke. A large number of population-based studies and intervention trials have demonstrated that the Mediterranean diet is associated with lower prevalence of vascular disease, obesity, arthritis, cancer, and age-associated cognitive decline. Many of these effects are the result of consumption of fruits, seeds, legumes and vegetables but olive oil is the chief dietary fat in Mediterranean countries and the main source of monounsaturated fatty acids, as well as an important source of beneficial polyphenols and other antioxidants. Considering the critical role of vascular factors in the pathogenesis of late-onset Alzheimer disease it seems appropriate to focus on disease modification through proven dietary therapy. The authors base their hypothesis on meta-analyses of epidemiological data, numerous experimental studies, and a comprehensive review of the mechanisms of action of extra-virgin olive oil and its components in the prevention of vascular disease. In addition, extra-virgin olive oil has had positive effects on experimental animal models of Alzheimer disease. We therefore propose that extra-virgin olive oil is a promising tool for mitigating the effects of adverse vascular factors and may be utilized for potential prevention of late-onset Alzheimer disease.

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.

The concept that diet, serum cholesterol and cardiovascular disease are causally related gave rise to the diet-heart hypothesis nearly 70 years ago. This hypothesis postulates that reducing dietary saturated fat reduces serum cholesterol, thereby reducing the risk of cardiovascular disease. Today, this concept has been transformed from a hypothesis into public health policy as current guidelines recommend reducing the intake of dietary saturated fat.1 Not all practitioners agree, however, and a reappraisal of the evidence may help resolve this controversy. Dr Ancel Keys first proposed the diet-heart hypothesis in the 1950s. Several years later, he published the Seven Countries Study that reported a strong correlation between dietary fat and coronary mortality in seven countries.2 His hypothesis rapidly gained support and by 1977 the US Senate Select Committee on Nutrition and Human Needs formally recommended that Americans should reduce their consumption of total and saturated fat.3 Many scientists disagreed and a vitriolic debate soon followed.4 Presently, the American Heart Association recommends ‘lowering intake of saturated fat and replacing it with unsaturated fats, especially polyunsaturated fats’ to reduce cardiovascular disease.5 Low-density lipoprotein-cholesterol is a cholesterol-containing multi-molecular complex often targeted for reduction because of its central role in atherosclerosis, yet cholesterol is essential for life as a key constituent of cell membranes and bile acids and as a precursor of …

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.

Objectives The purpose of this study was to relate risk factor changes during decades with 50-year coronary heart disease mortality in European cohorts of middle-aged men of the Seven Countries Study. Material and methods In the 1950s–early 1960s, nine cohorts of 6518 men aged 40–59 years were examined in five European countries. Smoking habits, systolic blood pressure and serum cholesterol were measured at entry and five times during the next 35 years and a comprehensive Risk Factor Change Score was created. Coronary heart disease mortality data was collected during a 50-year follow-up, modelled by the Weibull distribution, whose shape (Weibull shape) was related to the Risk Factor Change Score by linear regression. Results The Risk Factor Change Score showed slight declines in the Finnish and Dutch cohorts, moderate or large increases in the other cohorts. These effects were related to a decrease of smoking habits in all cohorts, an increase of blood pressure in all cohorts except East Finland, a decrease of serum cholesterol in Finland and the Netherlands, whereas serum cholesterol increases were slight in Italy and large in Serbia and Greece. Weibull distribution shape for coronary heart disease mortality showed slight deceleration in one Finnish and the Dutch cohorts, large acceleration in the Serbian and Greek cohorts. The correlation coefficient of the Risk Factor Change Score versus Weibull shape for the nine cohorts was 0.78 ( R2 = 0.60; p = 0.0132). Conclusions Spontaneous long-term changes of major coronary risk factor levels were associated with changes in the same direction of coronary heart disease mortality risk modelled by the Weibull distribution, expressing a kind of ‘natural experiment’ with an outcome that matches those of controlled preventive trials.

It is well established that what certain nutrients benefit our physical health. More recently there has been growing interest in the relationship between diet and brain health. The dietary pattern that has received the most interest is the Mediterranean diet. Many years have passed since the original Seven Countries study, which indicated that individuals living in the Mediterranean region had lower rates of death due to coronary heart disease compared to those from Northern Europe and the United States. This finding was ascribed to the dietary pattern that is commonly adhered to in that region. A diet high in fresh fruits, vegetables, breads, cereals, nuts, olive oil, legumes, fish, moderate consumption of dairy, poultry, red wine, and low consumption of red meat—the Mediterranean diet. Since then, adherence to this dietary pattern has been repeatedly linked to lower risk of mortality, cardiovascular disease, and the risk of developing dementia. This chapter explores the evidence for Mediterranean diet and its components in improving cognitive function and protecting against age-related cognitive decline.

Several areas of research into the prevention and treatment of obesity today can be traced to one or more of the scientific works pioneered by Ancel Keys between the 1930s to 1970s in fields that cut across the physiology of extremes and public health nutrition. These range from his classical studies into how body and mind respond to chronic exposure to hypoxia in "The Physiology of Life at High Altitudes" or to simulated famine under controlled laboratory conditions in "The Biology of Human Starvation", the impact of diet and lifestyle on cardiovascular morbidity and mortality in "The Seven Countries Study," to the "Indices of Relative Weight and Obesity" in which he identified what has since been the most widely utilized diagnostic tool to monitor obesity across populations worldwide and which he coined as the body mass index. The contribution of Ancel Keys to medical sciences through his observations, analytical approaches, and research output of his classic studies, and how these have (and continue) to impact on a plethora of current concepts in obesity research today, are embodied in the eight review articles that constitute this supplement reporting the proceedings of the 10th Fribourg Obesity Research Conference. The aim of this introductory paper is to put into perspective the legacy of Ancel Keys to current concepts that are encapsulated in these review articles that cover research areas that include (i) the diagnosis of obesity for health risks; (ii) the role of dietary fat types in the pathogenesis of obesity and cardiometabolic diseases; (iii) the rationale, efficacy and safety of low carbohydrate ketogenic diets, or the therapeutic potential of hypoxic conditioning, in weight management programs; (iv) the psychological and physiological basis of the "famine reaction" that counters therapeutic dieting and facilitates weight regain; and (v) the potential impact of weight cycling and yoyo dieting on risks for later obesity and cardiometabolic diseases.

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.

Introduction The metabolic syndrome (Met Sy) is a known cluster of risk factors (HTA, HLP, DM, BMI) that promotes overall vascular disease, however its real impact on overall, ischemic heart disease (IHD) and cerebrovascular disease (CVD) mortality remains debated. Material and methods The Seven Countries Study encompassed 12,763 participants who were healthy men over 40y at baseline and who underwent regular check ups every 5 years throughout over a 4 decades' span. Morbidity and mortality was adjudicated according to valid ICD and LPH coding. Results Using the IDF definition of the Metabolic Syndrome, 9,09% of participants were identified. In a multivariate analysis predictors for overall Mt were hypertension (p Conclusion Metabolic syndrome's role in atherosclerotic burden remains important, however whether its power is due to its respective components or their interactions remains to be an issue. The described results belong to an era where both IHD and CVD were considered a “male disease” women were spared of, so, further validation in the described cohorts is needed in an offspring fashion, however hypertension remains the driving force of both overall mortality as well as specific IHD and CVD ones, also previously demonstrated in the very same cohort to be more important in the setting of maternal family history of hypertension, than paternal one. MetSy in the SCS Funding Acknowledgement Type of funding source: None

Purpose of review To provide an update on dietary measures to lower levels of LDL-C and triglyceride and reduce cardiovascular (CVD) outcomes. Recent findings Fifty-year follow-up in the Seven Countries Study confirmed that cholesterol levels correlate with saturated fat intake and all-cause mortality and age at death. In the PURE study, refined carbohydrate increased CVD risk whereas saturated fat did not despite increasing LDL-C levels; limitations are discussed. Reports on CVD risk with eggs provide conflicting results. Plant-based diets with healthful complex carbohydrates reduced CVD. The REDUCE-IT trial lowered triglyceride 21.6% and reduced CVD events 26.1% with an omega-3 fatty acid, An omega-3 fatty acid index at least 4% with EPA and docosahexaenoic acid prevented coronary plaque progression. A clinician guide to counsel patients on nutrition and heart healthy diets was recently published. Summary Based on the evidence, individuals should continue to minimize saturated fats and refined carbohydrates, eliminate trans-fat and increase fruits, vegetables, whole grains, low-fat dairy, and fish or other omega-3 fatty acids. Adhering to a Mediterranean diet is strongly recommended because of lowering CVD and total mortality. High-dose omega-3 fatty acids lower triglyceride, reduce CVD and prevent coronary plaque progression.

Office white-coat effect tail (OWCET) is defined as a decrease of ≥10 mmHg in systolic blood pressure (SBP) between successive measurements after its waxing during an office visit. The influence of sex on the incidence of long-term major fatal and non-fatal cardiovascular events was studied in two Italian populational cohorts [from the Gubbio Study and the Italian Rural Areas of the Seven Countries Study (IRA)]. OWCET increased risk of cardiovascular disease (CVD) [HR: 1.591 (95% CI: 1.204-2.103)], coronary heart disease (CHD) [HR: 1.614 (95% CI: 1.037-2.512)] and stroke (STR) [HR: 1.696 (95% CI: 1.123-2.563)] events independently of age, serum and high density lipoprotein (HDL) cholesterol, cigarettes, body mass index (BMI) and SBP in women included in Gubbio study over an almost 20-year follow-up. However, risks of CVD, CHD or STR increased in men with OWCET neither in the Gubbio 20-year follow-up nor in the IRA 50-year follow-up. The correction of the regression dilutions bias between the first and the subsequent SBP measurements did not significantly change these outcomes. Primary care physicians should evaluate OWCET, especially in women, to improve stratification of long-term CVD, CHD and STR risks.

Introduction: Components of the metabolic syndrome (MetSy) have gone through myriad of changes ever since the initial cluster was defined. The Seven Countries Study taught us the basics of classical risk factors for atherosclerotic artery disease and their influence on both cardiovascular and cerebrovascular morbidity and mortality. Material and Methods: In a 3-continent, 7-country (USA, Japan, Greece, the Netherlands, Finland, Italy, and former Yugoslavia then, now Croatia and Serbia) sample of 12,763 participants -- all healthy men over 40 at entry -- systematic, quinquennial checkups were conducted over 4 decades and MetSy was defined using the IDF definition. ResultS: A total of 9,09% of participants were identified to have MetSy, while the detailed description of risk factors' combination is shown in Table 1 and Figure 1, below. Conclusion: The leading combination was hypertension (HTA), diabetes (DM) and dyslipidemia (HLP), while hypertension was the hallmark risk factor irrelevant of presence or absence of MetSy. The results of this study call for a contemporary comprehensive research involving both sexes that could elucidate better real life risk factors' relationships in aforementioned countries.

To study age at death (AD) in elderly men as a function of risk factors and morbid conditions in a 25-year follow-up. Men enrolled in the Seven Countries Study belonging to 8 cohorts in 4 European countries (Finland, The Netherlands, Italy and Serbia) were examined between 1984 and 1989 (aged 65–84 years) with measurement of some cardiovascular risk factors and recording of a few major morbid conditions. AD was measured after 25-year follow-up and used in multiple linear regression (MLR) models as dependent variable; while, risk factors and morbid conditions had the role of independent variables. Out of 2457 men, 2290 died during 25-year follow-up. Overall mean AD was of 82.0 years and slightly different across cohorts, the lowest being recorded in Finland. Age at entry examination and HDL cholesterol were directly associated with AD; while, blood pressure, heart rate, smoking habits and morbid conditions (major cardiovascular diseases, either independently or combined together with diabetes, chronic bronchitis, cancer and silent ECG abnormalities) were inversely related to AD. Body mass index had a parabolic relation with AD with longer survival for levels around 24 units; while, total serum cholesterol was not related to AD. However, only three independent variables were statistically significant when tested in each individual country (age, heart rate and stroke). In a MLR model, where a comorbidity score was entered as independent variable (everything else being equal), the presence of 1 morbid condition was associated with a reduced AD by 1.87 years that increased up to 6.39 years when 4 morbid conditions were present. AD seems a valuable indicator of all-cause mortality when the study population has reached or approached the extinction.

Since the emblematic “Seven Countries Study” of Ancel Keys and the emergence of the Mediterranean diet (MD) as a recognized food pattern, major nutritional changes have been noted in Mediterranean populations. War-torn countries and areas afflicted by poverty and the recent economic recession have increased the prevalence of food insecurity. A negative relationship has been demonstrated between MD and food insecurity, particularly in the Mediterranean region. Furthermore, the tendency of food-insecure persons to decrease the quality of their diet and choose less nutritious foods results in micronutrient inadequacies. A negative pattern seems to emerge in the Mediterranean countries as more people abandon the MD due to economic barriers, thwarting MD adherence. Based on the economic theory, the decreased income is associated with obesogenic diets and the consumption of energy-dense food. Promotion of the MD as a sustainable diet will help reduce the prevalence of food insecurity and provide the foundations of food security for posterity.

The Mediterranean diet was first described by the Seven Countries Study in the 1960s as a cardioprotective diet, as a pattern of eating that was traditionally prevalent among residents of the Mediterranean basin countries. Since then the Mediterranean dietary pattern has been extensively described and explored with respect to its health benefits and has been identified as one of the healthier diets in the world, being associated including in some cases causally as protective against cardiovascular diseases, type 2 diabetes mellitus, some cancer, mental health issues, cognitive decline, etc. While attempts have been made to explain the protective aspects of Mediterranean diet, research groups and foundations including the United Nations Educational, Scientific, and Cultural Organization (UNESCO) have extended the definition of Mediterranean diet to be a holistic entity: the Mediterranean lifestyle. The cornerstone of the Mediterranean lifestyle not only is based upon the traditional Mediterranean diet but also extends to include food preparation, food sharing, harvesting, eating locally and seasonally, and socializing often and with all age groups and social classes while eating together. Although these behaviors are integral aspects of Mediterranean culture, the Mediterranean lifestyle requires thorough investigation to be exported outside of its Mediterranean cradle and offer its protectiveness worldwide.

The Mediterranean Adequacy Index (MAI) is an a priori dietary score created within the experience of the Seven Countries Study (SCS) of Cardiovascular Diseases, exploiting data of its feasibility study carried out in 1957–60 in Nicotera (Southern Italy). It represents the shape of typical dietary habits common in those times along the shores of several Mediterranean countries. The MAI was computed by dividing the sum of the energy percentages of typical Mediterranean food groups (bread, cereals, legumes, potatoes, vegetables, fresh fruit, nuts, fish, wine, and vegetable oils) by the sum of the energy percentages of less typical Mediterranean food groups (milk, cheese, meat, eggs, animal fats and margarines, pastries, sugar, and sugar beverages). High levels of the MAI correspond to a higher adherence to the Mediterranean dietary habits. The MAI was strongly ecologically related to the 25-year coronary heart disease death rates of the 16 cohorts of the SCS (R = − 0.84), to the 50-year death rates for the same end point (R = − 0.91), and to the 50-year all-cause mortality of the same study, after adjustment for socioeconomic status (R = − 0.62). Moreover the MAI performed satisfactorily also when applied to individual data of the SCS and other international studies.

The Mediterranean diet, one of the best studied dietary patterns, developed as a result of sociocultural, political, religious, agricultural, and economic influences over time in a geographical region. The Seven Countries Study established the association between the eating patterns of Mediterranean countries with longevity and reduced risk of cardiovascular disease compared to northern European countries and the USA over follow-up for 25 years. Since that study numerous epidemiological studies support the health benefits and disease prevention effect of adherence to the Mediterranean diet. The dietary pattern associated with Mediterranean diet is based on olive oil (mainly extra-virgin or virgin olive oil) as the main source of fat, whole grains, legumes, fruits, vegetables, nuts, and fish, wine in moderation, and a moderate intake of lean fresh meat, and dairy products, which provide an important source of minerals, vitamins, antioxidants, mono- and polyunsaturated fatty acids, and fiber. The purpose of this chapter is to update on the available evidence of the benefits of the Mediterranean diet and the Mediterranean lifestyle in health through its impact on different chronic diseases, including cardiovascular diseases, metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and neurodegenerative diseases.

Purpose of review The Seven Countries Study (SCS) of Cardiovascular Diseases started midway last century and was the pioneer investigation of coronary heart disease (CHD) at international level. The 16 cohorts of middle-aged men enrolled in eight nations of seven countries allowed to show large differences of CHD incidence and mortality across different cultures, partly explained by average levels of serum cholesterol and dietary habits, that is, Western type patterns in the high-risk populations, and Mediterranean or Oriental type in Southern Europe and Japan. Later, critics to the validity of the study were largely based on fake news, wrong or distorted information uncritically transmitted in a cascade of media. Recent findings Recent analyses based on 45-50 years of follow-up showed and confirmed that diet patterns were associated with all-cause mortality and age at death; that multivariate coefficients of major risk factors of CHD were not heterogeneous across different populations and cultures; that analysis of competing risks of CHD versus other conditions identified serum cholesterol as the critical determinant; that true CHD manifestations had different determinants compared with Heart Diseases of Uncertain Etiology frequently confused with CHD. Summary The SCS can still teach investigators and scholars of cardiovascular epidemiology, if old contributions are carefully read and interpreted; it is still recognized as the seminal study in this area at international level although it had limits as any other study but represented the first step into the identification of the relationship of diet with CHD and mortality across populations, and of the Mediterranean diet.

Few people have influenced western eating patterns in the twentieth and early twenty-first centuries as much as physiologist and epidemiologist Ancel Keys (1904–2004). Keys not only developed the K...

The average life expectancy of the world population has increased remarkably in the past 150 years and it is still increasing. A long life is a dream of humans since the beginning of time but also a dream is to live it in good physical and mental condition. Nutrition research has focused on recent decades more on food combination patterns than on individual foods/nutrients due to the possible synergistic/antagonistic effects of the components in a dietary model. Various dietary patterns have been associated with health benefits, but the largest body of evidence in the literature is attributable to the traditional dietary habits and lifestyle followed by populations from the Mediterranean region. After the Seven Countries Study, many prospective observational studies and trials in diverse populations reinforced the beneficial effects associated with a higher adherence to the Mediterranean diet in reference to the prevention/management of age-associated non-communicable diseases, such as cardiovascular and metabolic diseases, neurodegenerative diseases, cancer, depression, respiratory diseases, and fragility fractures. In addition, the Mediterranean diet is ecologically sustainable. Therefore, this immaterial world heritage constitutes a healthy way of eating and living respecting the environment.

Culturally congruent dietary patterns have evolved with geographic and societal traditions and can be traced as far back as pre-Hellenistic Greece. Today, the modern Mediterranean diet (MDiet) is recognized internationally as an anti-obesogenic cardioprotective dietary model consisting of plant-based foods native to the Mediterranean basin, fish, olive oil, and an active lifestyle. With the assumption that obesity and heart disease rates adversely affected life expectancy, the MDiet was identified by Dr Ancel Keys as a primary characteristic among people-groups largely immune to these trends. Following extensive research on how food quality affected human performance, Keys engineered the largest ecologic investigation of dietary habits and their effects on heart disease and longevity known as the Seven Countries Study. A new understanding of how regionally and culturally specific diets affected entire populations led to the introduction of the MDiet to the global public health community. This historiographic portrait of Dr Keys describes his humble beginnings, highlights critical points in his career, discusses his seminal research into diet and culture as protective agents, and details his legacy as the pioneer of the modern MDiet.

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.

The Mediterranean diet is currently considered a healthy dietary pattern. It includes a great variety of foods, which are eaten in moderation and within a positive social environment. The generic term “Mediterranean diet” was born after the “Seven Countries Study” led by Ancel Keys around 1960. This dietary pattern is characterized by a high intake of fruits and vegetables, whole grains, legumes, nuts, fish, white meats and olive oil. It also includes moderate consumption of fermented dairy products, low intake of red meat and drinking wine with moderation during meals. Nutritionally, this diet is low in saturated fats and animal protein, high in antioxidants, fiber and monounsaturated fats, and exhibits an adequate omega-6/omega-3 fatty acid balance. The main bioactive compounds, which explain the health benefits of this dietary pattern, are antioxidants, fiber, monounsaturated and omega-3 fatty acids, phytosterols and probiotics. This diet is not exclusively confined to the Mediterranean Basin. Central Chile has a Mediterranean climate and our agriculture and culinary traditions are similar to those found in Mediterranean countries. Therefore, it is fundamental to increase awareness about the richness of our natural produce as well as our culinary culture, which may bring many health benefits and improve the quality of life in our population.

Using data from the Seven Countries Study of Cardiovascular Diseases, the first study to conduct international comparisons of men in different European, USA, and Japanese cohorts, we examined the effect of diet-associated inflammation on prediction of coronary heart disease-, other major cardiovascular disease- and all-cause mortality after 50-years of follow-up. The energy-adjusted Dietary Inflammatory Index was used to quantify the effect of diet on systemic inflammation. Positive linear correlations were observed between the cohort-average energy-adjusted Dietary Inflammatory Index score and both overall death rates (R = 0.61, p = 0.0114) and major cardiovascular disease mortality rates (R = 0.51, p = 0.0337) but not cancer. Correlations for all-cause mortality were higher when the Belgrade outlier cohort was omitted (R = 0.72, p = 0.0024) or when analyses were adjusted for socioeconomic status (R = 0.67, p = 0.0065). There was also a significant reverse correlation between energy-adjusted Dietary Inflammatory Index score and age at death (R = –0.50 to –0.68, p = 0.0480 to 0.0012). Adjusting for systolic blood pressure, cholesterol, and smoking habits did not modify these correlations that were still significant. With control for these covariates a significant correlation emerged for coronary heart disease. Results obtained using a 25-year follow-up to allow unprojected data from all cohorts were similar. Results from this long-term follow-up study are consistent with a recommendation to increase consuming an anti-inflammatory diet characterized by high concentrations of fruits and vegetables and low consumption of simple carbohydrates and fats.

To assess the impact of sex on office white-coat effect tail (OWCET), the waning of systolic blood pressure (SBP) after its waxing during office visit, on the incidence of long-term major fatal and non-fatal events in two Italian residential cohorts [from the Gubbio Study and the Italian Rural Areas of the Seven Countries Study (IRA)]. There were 3565 persons (92 with missing data, 44% men, 54 ± 11 years) included in the Gubbio and 1712 men (49 ± 5 years) in the IRA studies. OWCET was defined as a decrease of ≥10 mmHg in SBP between successive measurements with slight measurement differences between the two cohorts. Cardiovascular (CVD), coronary heart disease (CHD) and stroke (STR) incidences were considered. Over an approximately 20-year follow-up, women with OWCET had an increased risk of CVD [HR: 1.591 (95%CI: 1.204–2.103)], CHD [HR: 1.614 (95%CI: 1.037–2.512)] and STR [HR: 1.696 (95%CI: 1.123–2.563)] events independently of age, serum and HDL cholesterol, cigarettes, BMI and SBP in the Gubbio study. However, there was no increased risk of CVD, CHD or STR in men with OWCET neither in the Gubbio 20-year follow-up nor in the IRA 50-year follow-up. These results were not modified significantly by the correction of the regression dilutions bias between the first and the subsequent SBP measurements. Thus, in primary care, OWCET should be actively evaluated in women as it can improve stratification of long-term CVD, CHD and STR risks.

The Mediterranean diet (MedDiet) represents the crystallisation of the centuries-old cooking legacies of different civilisations. The association of the MedDiet with longevity and low cardiovascular risk prompted the Seven Countries Study, which provided epidemiological evidence on the health effects of diet. This led to further studies, both epidemiological and interventional. Scales to measure adherence as well as studies of food components have consolidated a body of knowledge that is of great interest to institutions and governmental agencies. The recognition of its benefits for health has made the widespread introduction of the MedDiet an urgent challenge. Parallel efforts are being made to extend research through experimental and clinical studies. The purpose of this review is to present the historical background of the MedDiet, the main steps leading to the recognition of its health benefits, and the current strategy to facilitate its global implementation.

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.

In 1972 Body Mass Index, BMI was put forth by physiologist Ancel Keys in his analysis of Seven Countries Study heart disease epidemiological data as the best available measure of obesity. This work culminated more than 20 years of effort by Keys to discredit the accepted measure of obesity, weight relative to height, along with a major public health campaign in the United States to fight heart disease through weight control. Here, I retrace his campaign to replace weight as a measure of obesity and analyze its methodology and relationship to the broader research field of heart disease epidemiology. I also explore why the epidemiological community accepted BMI despite Keys's failure to demonstrate that either it or adiposity (body fat content), were superior as predictors of heart disease-one of the Seven Countries Study's central aims.

Background\ud \ud The Seven Countries study in the 1960s showed that populations in the Mediterranean region experienced lower coronary heart disease (CHD) mortality probably as a result of different dietary patterns. Later observational studies have confirmed the benefits of adherence to a Mediterranean dietary pattern on cardiovascular disease (CVD) risk factors but clinical trial evidence is more limited.\ud \ud Objectives\ud \ud To determine the effectiveness of a Mediterranean-style dietfor the primary and secondary prevention of CVD. \ud \ud Search methods\ud \ud We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9);MEDLINE (Ovid, 1946 to 25 September 2018); Embase (Ovid, 1980 to2018 week 39); Web of Science Core Collection (ThomsonReuters, 1900 to 26 September 2018); DARE Issue 2 of 4, 2015 (Cochrane Library); HTA Issue 4 of 4, 2016 (Cochrane Library); NHSEED Issue 2 of 4, 2015 (Cochrane Library). We searched trial registers and applied no language restrictions.\ud \ud Selection criteria\ud \ud We selected randomised controlled trials (RCTs) in healthy adults and adults at high risk of CVD (primary prevention) and those with established CVD (secondary prevention). Both of the following key components were required to reach our definition of a Mediterranean-style diet: high monounsaturated/saturated fat ratio (use of olive oil as main cooking ingredient and/or consumption of other traditional foods high in monounsaturated fats such as tree nuts) and a high intake of plant-based foods, including fruits, vegetables and legumes. Additional components included: low to moderate red wine consumption; high consumption of whole grains and cereals; low consumption of meat and meat products and increased consumption of fish; moderate consumption of milk and dairy products. The intervention could be dietary advice, provision of relevant foods, or both. The comparison group received either no intervention, minimal intervention, usual care or another dietary intervention. Outcomes included clinical events and CVD risk factors. We included only studies with follow-up periods of three months or more defined as the intervention period plus post intervention follow-up.\ud \ud Data collection and analysis\ud \ud Two review authors independently assessed studies for inclusion, extracted data and assessed risk of bias. We conducted four maincomparisons:\ud \ud 1. Mediterranean dietary intervention versus no intervention or minimal intervention for primary prevention;\ud 2. Mediterranean dietary intervention versus another dietary intervention for primary prevention;\ud 3. Mediterranean dietary intervention versus usual care forsecondary prevention;\ud 4. Mediterranean dietary intervention versus another dietary intervention for secondary prevention. \ud \ud Main results\ud \ud In this substantive review update, 30 RCTs (49 papers) (12,461participants randomised) and seven ongoing trials met our inclusion criteria. The majority of trials contributed to primary prevention: comparisons 1 (nine trials) and 2 (13 trials). Secondary prevention trials were included for comparison 3 (two trials) and comparison 4 (four trials plus an additional two trials that were excluded from the main analyses due to published concerns regarding the reliability of the data).Two trials reported on adverse events where these were absent or minor (low- to moderate-quality evidence). No trials reported on costs or health-related quality of life. \ud \ud Primary prevention\ud \ud The included studies for comparison 1 did not report on clinical endpoints (CVD mortality, total mortality or non-fatal endpoints such as myocardial infarction or stroke). The PREDIMED trial (included in comparison 2) was retracted and re-analysed following concerns regarding randomisation at two of 11 sites. Low-quality evidence shows little or no effect of the PREDIMED (7747 randomised)intervention (advice to follow a Mediterranean diet plus supplemental extra-virgin olive oil or tree nuts) compared to a low-fat diet onCVD mortality (hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.50 to 1.32) or total mortality (HR 1.0, 95% CI 0.81 to 1.24)over 4.8 years. There was, however, a reduction in the number of strokes with the PREDIMED intervention (HR 0.60, 95% CI 0.45to 0.80), a decrease from 24/1000 to 14/1000 (95% CI 11 to 19), moderate-quality evidence). For CVD risk factors for comparison 1there was low-quality evidence for a possible small reduction in total cholesterol (-0.16 mmol/L, 95% CI -0.32 to 0.00) and moderate-quality evidence for a reduction in systolic (-2.99 mmHg (95% CI -3.45 to -2.53) and diastolic blood pressure (-2.0 mmHg, 95% CI -2.29 to -1.71), with low or very low-quality evidence of little orno effect on LDL or HDL cholesterol or triglycerides. For comparison2 there was moderate-quality evidence of a possible small reduction in LDL cholesterol (-0.15 mmol/L, 95% CI -0.27 to -0.02) andtriglycerides (-0.09 mmol/L, 95% CI -0.16 to -0.01) with moderateor low-quality evidence of little or no effect on total or HDLcholesterol or blood pressure.\ud \ud Secondary prevention\ud \ud For secondary prevention, the Lyon Diet Heart Study (comparison 3) examined the effect of advice to follow a Mediterranean diet and supplemental canola margarine compared to usual care in 605 CHD patients over 46 months and there was low-quality evidence of a reduction in adjusted estimates for CVD mortality (HR 0.35, 95% CI 0.15 to 0.82) and total mortality (HR 0.44, 95% CI 0.21 to0.92) with the intervention. Only one small trial (101 participants) provided unadjusted estimates for composite clinical endpoints for comparison 4 (very low-quality evidence of uncertain effect). For comparison 3 there was low-quality evidence of little or no effect of a Mediterranean-style diet on lipid levels and very low-quality evidence for blood pressure. Similarly, for comparison 4 where only two trials contributed to the analyses there was low or very low-quality evidence of little or no effect of the intervention on lipid levels or blood pressure. \ud \ud Authors’ conclusions\ud \ud Despite the relatively large number of studies included in this review, there is still some uncertainty regarding the effects of a Mediterranean-style diet on clinical endpoints and CVD risk factors for both primary and secondary prevention. The quality of evidence for the modest benefits on CVD risk factors in primary prevention is low or moderate, with a small number of studies reporting minimal harms. There is a paucity of evidence for secondary prevention. The ongoing studies may provide more certainty in the future.\ud