The Seven Countries Study is an epidemiological longitudinal study directed by Ancel Keys at what is today the University of Minnesota Laboratory of Physiological Hygiene & Exercise Science (LPHES). Begun in 1956 with a yearly grant of US$200,000 from the U.S. Public Health Service, the study was first published in 1978 and then followed up on its subjects every five years thereafter.
As the world's first multicountry epidemiological study, it systematically examined the relationships between lifestyle, diet, coronary heart disease and stroke in different populations from different regions of the world. It directed attention to the causes of coronary heart disease and stroke, but also showed that an individual’s risk can be changed.
Writing in 1975, project officer Henry Blackburn identified two "strikingly polar attitudes", characterising them as persisting "academic" and "pragmatic" views with "much talk from each and little listening between." [1]
In the 1940s, a University of Minnesota researcher, Ancel Keys, postulated that the apparent epidemic of heart attacks in middle-aged American men was related to their mode of life and possibly modifiable physical characteristics. He first explored this idea in a group of Minnesota business and professional men (executives aged 45 to 55) that he recruited into a prospective study in 1947, the first of many cohort studies eventually mounted internationally. The U.S. Public Health Service agreed to fund the study (and then set up and proceeded to fund the Framingham Heart Study on a larger scale). The Minnesota men were followed through 1981 and the first major report appeared in 1963 after the fifteen-year follow-up study. [2] [3]
The study contributed much to survey methods and confirmed larger studies that reported earlier on the predictive value for heart attack of several characteristics, the now-traditional risk factors of blood pressure and blood cholesterol level and cigarette smoking. Keys traveled widely with his wife Margaret who tested people's serum cholesterol. They sent their samples back to Minnesota for analysis. In 1952, Keys's hypothesis that coronary heart disease could be related to diet was first published in Voeding in The Netherlands. [4] His work in post-wartime Naples led him to seek organization and funding for studies of different populations, as did his subsequent work in Uganda; Cape Town, South Africa; Sardinia; Bologna; and Ilomantsi, Finland; and with Japanese men living in Hawaii and in Japan. He decided to concentrate on men living in villages, rather than those in cities where the population moved around frequently. [3]
In the mid-1950s, with improved methods and design, Keys recruited collaborating researchers in seven countries to mount the first cross-cultural comparison of heart attack risk in populations of men engaged in traditional occupations in cultures contrasting in diet, especially in the proportion of fat calories of different composition, the Seven Countries Study still under observation today.
The Seven Countries Study was formally started in fall 1958 in Yugoslavia. In total, 12,763 males, 40–59 years of age, were enrolled as 16 cohorts, in seven countries, in four regions of the world (United States, Northern Europe, Southern Europe, Japan). One cohort is in the United States, two cohorts in Finland, one in the Netherlands, three in Italy, five in Yugoslavia (two in Croatia, and three in Serbia), two in Greece, and two in Japan. The entry examinations were performed between 1958 and 1964 with an average participation rate of 90%, lowest in the US, with 75% and highest in one of the Japanese cohorts, with 100%. [5] The study has continued for more than 50 years.
The Seven Countries Study suggested that the risk and rates of heart attack and stroke (CVR), both at the population level and at the individual level, correlated directly and independently to the level of total serum cholesterol, in seven sampled out countries. It demonstrated that the correlation between blood cholesterol level and coronary heart disease (CHD) risk from 5 to 40 years follow-up is found consistently across different specially selected cultures in these seven countries. Cholesterol and obesity correlated with increased mortality from cancer. [6] [7] [8] The Seven Countries Study suggested that elevated blood pressure (hypertension) was correlated with risk of coronary heart disease and stroke. It showed that the mortality rate after a coronary heart disease event or stroke was associated with the level of hypertension. In several cohorts of the study, stroke deaths exceeded deaths from coronary heart disease. [9] [10] It hinted that differences in overall mortality between the different regions of the seven countries are largely associated with variation in cardiovascular mortality. [11] Coronary deaths in the United States and Northern Europe greatly exceeded those in Southern Europe, even when controlled for age, cholesterol, blood pressure, smoking, physical activity, and weight.
The Seven Countries Study was investigated further in regard to an eating pattern loosely characterized as the Mediterranean Diet. [12] [13] [14] [11] [15] What exactly is meant by "Mediterranean Diet" today, was detailed by Antonia Trichopoulou (wife of Dimitrios Trichopoulos), [16] and Anna Ferro-Luzzi. [17] The diet was publicized and popularized by Greg Drescher of the Oldways Preservation and Exchange Trust and by Walter Willett of the Harvard School of Public Health. [18] [19] [20] [21] [22]
The Seven Countries Study also showed that the slowly changing habits of a population in the Mediterranean region, from a healthy, active lifestyle and diet, to a less active lifestyle and a diet influenced by the Western pattern diet, significantly correlated with increased risk of heart disease. [23] [24] Meanwhile, it has been confirmed by other researchers that there is an inverse association between adherence to the Mediterranean Diet and the incidence of fatal and non- fatal heart disease in initially healthy middle-aged adults in the Mediterranean region. [25]
The Seven Countries Study, along with other studies, e.g., the Framingham Heart Study and the Nurses' Health Study, showed the importance of overweight, obesity and regular exercise as health issues. [26] [27] [28] [29] It showed a correlation between good cardiovascular health and dementia in the general population. It also showed that cardiovascular risk factors in mid life are significantly associated with increased risk of dementia death later in life. [30] It indicated that cigarette smoking is a highly significant predictor of the development of coronary heart disease, leading to excess rates of angina pectoris, myocardial infarction (MI) and coronary death, along with other studies about smoking, e.g., the Framingham Heart Study and the British Doctors Study. [31] [32] [33] [34]
Scientists differed on the best predictors of heart disease. In 1950 in Science , John Gofman described separating lipoproteins into different densities in the ultracentrifuge. In 1952 as part of a panel with Keys, Gofman agreed that reducing fat in the diet might help some heart patients [35] (and in this same issue of Circulation Keys explained that dietary cholesterol is not a factor in humans [36] ). In 1956 Gofman wrote that an atherogenic index (the combined levels of LDL and VLDL) predicted atherosclerosis and heart disease. [37] In 1958 he wrote, "The serum cholesterol measurement can be a dangerously misleading guide in evaluation of the effect of diet upon the serum lipids." [38]
Jacob Yerushalmy and Herman E. Hilleboe pointed out that Keys had selected six countries out of 21 for which data were available. Analysis of the full dataset made the analysis between fat intake and heart disease less clear. [39] In 1957, when they published their critique, Yerushalmy and Hilleboe called Keys's work a "tenuous association". [40] Published in 1973 and including his critique of Keys's work, [41] Raymond Reiser found methodological and interpretational errors in a review of forty feeding trials of the relationship between saturated fat and circulating lipoproteins, notably confounding with trans-fatty acids. [42]
George V. Mann, writing in the New England Journal of Medicine in 1977, dismissed Keys's 1953 Mt. Sinai address about the ecologic correlation of diet fat and coronary disease as exhibiting "naïveté ... [that] is now a classroom demonstration.", [43] he did not say that the lipid theory is "the greatest scam in the history of medicine" [43] [44] ). Mann studied the mainly meat diet of Alaskan Eskimos, Congolese pygmies, and the Maasai of Tanzania and Kenya, and thought other factors like lack of exercise were responsible for heart disease. [45] Yet contrary to Mann's assertion that despite wide official recommendations for dietary change “the [coronary heart disease (CHD)] epidemic continues unabated, cholesteremia in the population is unchanged, and clinicians are unconvinced of efficacy”, [43] the age-specific CHD death rate in the United States had by that time been on a steady 3% annual decline since the late 1960s. [46]
John Yudkin thought that sugar, not fat, was at the root of heart disease and other human ills. Keys wrote and promoted his disagreement in 1971. [47] The next year Yudkin retired to write Pure, White and Deadly . [48]
Robert Lustig criticized that Keys cherry-picked seven of 22 countries; consumption of trans-fat peaked in the 1960s and Keys failed to separate them out; results for Japan and Italy could be explained by either low saturated fat consumption or by low sugar consumption; and Keys wrote that sucrose and saturated fat were intercorrelated but failed to perform the sucrose half of his multivariate correlation analysis. [49] However, in his later monograph of 1980, Keys included multivariate regressions in which sugar is added to the regression and saturated fat is controlled for. In this regression, Keys found that sugar was not statistically significantly related to incidence of heart disease when dietary saturated fat was controlled for. [5] Today, sugar intake is known to increase the risk of diabetes mellitus, and increased dietary intake of sugar is known to be associated with higher blood pressure, unfavorable blood lipids and cardiometabolic risks. [50] [51] However, a 2010 conference debate of the American Dietetic Association expressed concern over the health risks of replacing saturated fats in the diet with refined carbohydrates, which carry a high risk of obesity and heart disease, particularly at the expense of polyunsaturated fats which may have health benefits. [52]
In September 2014, Frank Hu led the 2015 Dietary Guidelines Advisory Committee's report on saturated fat and cardiovascular disease, and Alice H. Lichtenstein said that the consensus is that a low-fat diet is "probably not a good idea" and that it might induce dyslipidemia. She said that the guidelines had changed (formerly recommending low fat, and now moderate fat) in 2000, and that the American Heart Association and the National Heart, Lung, and Blood Institute had revised guidelines as of 2000. [53] The group's Scientific Report of the 2015 Dietary Guidelines Advisory Committee says the average person in the U.S. consumes too much saturated fat. "Sources of saturated fat should be replaced with unsaturated fat, particularly polyunsaturated fatty acids (PUFA)." [54] [55]
A meta-analysis in March 2014 met with controversy, finding that "current evidence does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total saturated fats", with Walter C. Willett continuing to defend reduced saturated fat in the diet. It was later corrected. [56] [57] As of 2017, the American Heart Association recommends reducing or replacing saturated fat with products containing monounsaturated and polyunsaturated fats to reduce the risk of cardiovascular diseases. [58]
On August 1, 2017, the True Health Initiative released a 65-page white paper, correcting what they felt were historical inaccuracies and errors that low-carb advocates have perpetuated: "Ancel Keys and the Seven Countries Study: An Evidence-based Response to Revisionist Histories" [59] They argued against four claims: that countries were selected and excluded based on desired outcome (as posited by Robert Lustig in his viral video); France was purposefully excluded; dietary data in Greece taken during Lent introduced a distortion; and that sugar was not considered as a possible contributor to coronary heart disease.
Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic plaque in the arteries of the heart. It is the most common of the cardiovascular diseases. Types include stable angina, unstable angina, and myocardial infarction.
Cholesterol is the principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.
In nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such compounds, most commonly those that occur in living beings or in food.
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. These lesions may lead to narrowing of the arterial walls due to buildup of atheromatous plaques. At onset there are usually no symptoms, but if they develop, symptoms generally begin around middle age. In severe cases, it can result in coronary artery disease, stroke, peripheral artery disease, or kidney disorders, depending on which body parts(s) the affected arteries are located in the body.
Ancel Benjamin Keys was an American physiologist who studied the influence of diet on health. In particular, he hypothesized that replacing dietary saturated fat with polyunsaturated fat reduced cardiovascular heart disease. Modern dietary recommendations by health organizations, systematic reviews, and national health agencies corroborate this.
A saturated fat is a type of fat in which the fatty acid chains have all single bonds. A fat known as a glyceride is made of two kinds of smaller molecules: a short glycerol backbone and fatty acids that each contain a long linear or branched chain of carbon (C) atoms. Along the chain, some carbon atoms are linked by single bonds (-C-C-) and others are linked by double bonds (-C=C-). A double bond along the carbon chain can react with a pair of hydrogen atoms to change into a single -C-C- bond, with each H atom now bonded to one of the two C atoms. Glyceride fats without any carbon chain double bonds are called saturated because they are "saturated with" hydrogen atoms, having no double bonds available to react with more hydrogen.
The French paradox is an apparently paradoxical epidemiological observation that French people have a relatively low incidence of coronary heart disease (CHD), while having a diet relatively rich in saturated fats, in apparent contradiction to the widely held belief that the high consumption of such fats is a risk factor for CHD. The paradox is that if the thesis linking saturated fats to CHD is valid, the French ought to have a higher rate of CHD than comparable countries where the per capita consumption of such fats is lower.
The Mediterranean diet is a diet inspired by the eating habits and traditional food typical of southern Spain, southern Italy, and Crete, and formulated in the early 1960s. It is distinct from Mediterranean cuisine, which covers the actual cuisines of the Mediterranean countries. While inspired by a specific time and place, the "Mediterranean diet" was later refined based on the results of multiple scientific studies.
Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease, and venous thrombosis.
Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia, hyperlipoproteinemia, and dyslipidemia.
Dyslipidemia is a metabolic disorder characterized by abnormally high or low amounts of any or all lipids or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular diseases (ASCVD), which include coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for ASCVD, abnormal levels don't mean that lipid lowering agents need to be started. Other factors, such as comorbid conditions and lifestyle in addition to dyslipidemia, is considered in a cardiovascular risk assessment. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin resistance can also lead to dyslipidemia. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.
Stanol esters is a heterogeneous group of chemical compounds known to reduce the level of low-density lipoprotein (LDL) cholesterol in blood when ingested, though to a much lesser degree than prescription drugs such as statins. The starting material is phytosterols from plants. These are first hydrogenated to give a plant stanol which is then esterified with a mixture of fatty acids also derived from plants. Plant stanol esters are found naturally occurring in small quantities in fruits, vegetables, nuts, seeds, cereals, legumes, and vegetable oils.
A healthy diet is a diet that maintains or improves overall health. A healthy diet provides the body with essential nutrition: fluid, macronutrients such as protein, micronutrients such as vitamins, and adequate fibre and food energy.
Phytosterols are phytosteroids, similar to cholesterol, that serve as structural components of biological membranes of plants. They encompass plant sterols and stanols. More than 250 sterols and related compounds have been identified. Free phytosterols extracted from oils are insoluble in water, relatively insoluble in oil, and soluble in alcohols.
The National Heart Foundation of Australia is a charity established in 1959. Its activities have been funding cardiovascular research, supporting health professionals in their practice, developing health promotion activities, informing and educating the public and assisting people with cardiovascular disease. It describes its mission as "to reduce heart disease and improve the heart health and quality of life of all Australians through our work in Risk Reduction, Support, Care and Research."
The lipid hypothesis is a medical theory postulating a link between blood cholesterol levels and the occurrence of cardiovascular disease. A summary from 1976 described it as: "measures used to lower the plasma lipids in patients with hyperlipidemia will lead to reductions in new events of coronary heart disease". It states, more concisely, that "decreasing blood cholesterol [...] significantly reduces coronary heart disease".
The Dietary Approaches to Stop Hypertension or the DASH diet is a diet to control hypertension promoted by the U.S.-based National Heart, Lung, and Blood Institute, part of the National Institutes of Health (NIH), an agency of the United States Department of Health and Human Services. The DASH diet is rich in fruits, vegetables, whole grains, and low-fat dairy foods. It includes meat, fish, poultry, nuts, and beans, and is limited in sugar-sweetened foods and beverages, red meat, and added fats. In addition to its effect on blood pressure, it is designed to be a well-balanced approach to eating for the general public. DASH is recommended by the United States Department of Agriculture (USDA) as a healthy eating plan. The DASH diet is one of three healthy diets recommended in the 2015–20 U.S. Dietary Guidelines, which also include the Mediterranean diet and a vegetarian diet. The American Heart Association (AHA) considers the DASH diet "specific and well-documented across age, sex and ethnically diverse groups."
The chronic endothelial injury hypothesis is one of two major mechanisms postulated to explain the underlying cause of atherosclerosis and coronary heart disease (CHD), the other being the lipid hypothesis. Although an ongoing debate involving connection between dietary lipids and CHD sometimes portrays the two hypotheses as being opposed, they are in no way mutually exclusive. Moreover, since the discovery of the role of LDL cholesterol (LDL-C) in the pathogenesis of atherosclerosis, the two hypotheses have become tightly linked by a number of molecular and cellular processes.
The Israeli paradox is an apparently paradoxical epidemiological observation that Israeli Jews have a relatively high incidence of coronary heart disease (CHD), despite having a diet relatively low in saturated fats, in apparent contradiction to the widely held belief that the high consumption of such fats is a risk factor for CHD. The paradox is that if the thesis linking saturated fats to CHD is valid, the Israelis ought to have a lower rate of CHD than comparable countries where the per capita consumption of such fats is higher.
Frank B. Hu is a Chinese American nutrition and diabetes researcher. He is Chair of the Department of Nutrition and the Fredrick J. Stare Professor of Nutrition and Epidemiology at the Harvard T.H. Chan School of Public Health, and Professor of Medicine at the Harvard Medical School.
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