Seven Countries Study

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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.[1]

As the world's first[2] 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.

As of 2016, heated scientific debate continues. Project officer Henry Blackburn wrote in 1975, "Two strikingly polar attitudes persist on this subject, with much talk from each and little listening between."[3] Ian Leslie quotes a sympathetic colleague at the University of Minnesota who said Keys was "critical to the point of skewering”.[4]

History[edit]

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.[5][6]

The study contributed much to survey methods and confirmed the results of larger studies that reported earlier on the predictive value for heart attack of several characteristics measured in health, 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.[7] Keys's 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.[6]

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 USA, with 75% and highest in one of the Japanese cohorts, with 100%.[8] The Seven Countries Study has continued for more than 50 years.

Major findings[edit]

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.[9][10][11] 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.[12][13] It hinted that differences in overall mortality between the different regions of the seven countries are largely associated with variation in cardiovascular mortality.[14] 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.[15][16][17][14][18] What exactly is meant by "Mediterranean Diet" today, was detailed by Antonia Trichopoulou (wife of Dimitrios Trichopoulos),[19] and Anna Ferro-Luzzi.[20] 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.[21][22][23][24][25][26]

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.[27][28] 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.[29]

The Seven Countries Study, along with other studies, e.g. the Framingham Heart Study, Nurses' Health Study, portended the importance of overweight, obesity, and regular exercise as health issues.[30][31][32][33] 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.[34] 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.[35][36][37][38]

Criticism[edit]

Early criticism[edit]

Scientists differed on the best predictors of heart disease. In 1950 in Science, John Gofman described separating lipoproteins into different densities in the University of California, Berkeley, ultracentrifuge.[39] In 1952 as part of a panel with Keys, Gofman agreed that reducing fat in the diet might help some heart patients[40] (and in this same issue of Circulation Keys explained that dietary cholesterol is not a factor in humans[41]). In 1956 Gofman wrote that an atherogenic index (the combined levels of LDL and VLDL) predicted atherosclerosis and heart disease.[42] 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."[43]

Some offered hypotheses opposed to Keys. In 1966, based on their work and writing since 1956, George Campbell and Thomas L. Cleave published Diabetes, Coronary Thrombosis and the Saccharine Disease. They argued that the chronic Western diseases such as diabetes, heart disease, obesity, peptic ulcers and appendicitis are caused by one thing: "refined carbohydrate disease".[44] In 1957 a distinguished pioneer in lipid research, Edward H. "Pete" Ahrens Jr. warned of oversimplifying the problem of diet and heart disease, saying the cause could be fat and cholesterol or it could be carbohydrates and triglycerides. Until evidence was produced, he questioned "the wisdom of prescribing low-fat diets for the general population."[45]

Even before the study had begun, there had been criticism of its methods. Jacob Yerushalmy and Herman E. Hilleboe pointed out that, for an earlier study demonstrating this association (Atherosclerosis, a problem in newer public health), 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.[46] In 1957 when they published their critique,[47] Yerushalmy and Hilleboe seemed to some to be lecturing, "the association between the percentage of fat calories... and mortality from... heart disease is not valid" and then they call Keys's work a "tenuous association".[48] Keys, who was one of the first nutrition epidemiologists, wrote in every journal article that "causal relationships are not claimed". His reaction was to mount the Seven Countries Study, the first multicountry epidemiological study ever done.[49]

Contemporary criticism[edit]

Several scientists stepped forward at the time to disagree with Keys's conclusions. Published in 1973 and including his critique of Keys's work,[50] 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.[51] Ahrens found separately with Margaret Albrink that triglycerides mattered in coronary disease more than total cholesterol, and came to think that carbohydrates cause heart disease and not fats.[52] George V. Mann, writing in the New England Journal of Medicine (NEJM) 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."[53] (On the other hand, although he is widely misquoted to this day (for example in Breitbart[54]), Mann did not say that the lipid theory is "the greatest scam in the history of medicine"[53][55]). 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.[56] 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”,[53] in fact 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.[57]

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.[58] The next year Yudkin retired to write Pure, White and Deadly.[59]

Debate since 2000[edit]

Controversy continues about the study itself,[60] and about the strength and causality of the association between dietary fat and heart mortality, particularly as the study of cholesterol has become more sophisticated.[61]

In 2000, Uffe Ravnskov (MD, PhD) published his book The Cholesterol Myths[62] and went on to found The International Network of Cholesterol Skeptics.[63]

In a 2001 article in Science magazine entitled Nutrition: The Soft Science of Dietary Fat, Gary Taubes wrote "it is still a debatable proposition whether the consumption of saturated fats above recommended levels (..) by anyone who's not already at high risk of heart disease will increase the likelihood of untimely death (..) [n]or have hundreds of millions of dollars in trials managed to generate compelling evidence that healthy individuals can extend their lives by more than a few weeks, if that, by eating less fat".[64][65] A New York Times Magazine article entitled "What if It's All Been a Big Fat Lie?" followed in 2002.[66] A further critical analysis of the Seven Countries Study was undertaken by Taubes in his bestselling book Good Calories, Bad Calories (2007)[67] which was followed by Why We Get Fat in 2010.[68] In Good Calories, Bad Calories, Taubes wrote that the Seven Countries Study "was fatally flawed (..) Keys chose seven countries he knew in advance would support his hypothesis (..) [that] coronary heart disease is strongly influenced by the fats in the diet (..) [n]o consideration was given to alternative hypothesis."[69] In his 2016 book The Case against Sugar, Taubes states that "of all the factors measured in these populations, the two that tracked best with heart disease—as Yudkin might have predicted—were sugar and saturated fat (..) and because populations in the study that ate a lot of one tended also to eat a lot of the other, Keys now suggested that this was ″adequate to explain the observed relationship between sucrose and [coronary heart disease] without recourse to the idea that sucrose″ (..) caused it. This was speculation (..) researchers typically assumed that if Keyes was right, Yudkin was wrong, and vice versa (..) [w]hen researchers realized that the French had relatively low rates of heart disease despite a diet that was rich in saturated fats, they wrote it off as an inexplicable ″paradox,″ and ignored the fact that the French traditionally consumed far less sugar than did populations—the Americans and British, most notably—in which coronary disease seemed to be a scourge."[70]

In his 2009 "viral video" Sugar: The Bitter Truth,[71] Robert Lustig (MD, PhD) criticized Keys' Seven Countries Study.[72] Lustig gave details in his book Fat Chance: 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.[73] 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.[8] 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.[74][75][76] Albeit, 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.[77]

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.[78] 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."[79][80]

A meta-analysis in March 2014 met with controversy and was corrected, it found 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.[81][82] As of 2017, the American Heart Association recommends that saturated fat be reduced or replaced by products containing monounsaturated and polyunsaturated fats to reduce the risk of cardiovascular diseases.[83]

Notes[edit]

  1. ^ Taubes, p. 31.
  2. ^ Teicholz, p. 36.
  3. ^ Gary Taubes quotes Blackburn in Good Calories, Bad Calories p. 22, from: Blackburn Henry (1975). "Contrasting Professional Views on Atherosclerosis and Coronary Disease". N Engl J Med. 292: 105–107. doi:10.1056/NEJM197501092920214. PMID 1109429. 
  4. ^ Leslie, Ian. "The sugar conspiracy" "The Guardian", London, 7 April 2016. Retrieved on 9 April 2016.
  5. ^ Keys A, Taylor HL, Blackburn H, Brozek J, Anderson JT, Simonson E (1963). "Coronary Heart Disease among Minnesota Business and Professional Men Followed Fifteen Years". Circulation. 28: 381–95. doi:10.1161/01.cir.28.3.381. PMID 14059458. 
  6. ^ a b Keys, Ancel in Kromhout, Daan, Menotti, Alessandro, and Blackburn, Henry (eds.) (1993). "ISBN is invalid: 90-6960-048-x". The Seven Countries Study: A Scientific Adventure in Cardiovascular Disease Epidemiology. Utrecht, The Netherlands: printed by Brouwer Offset bv. pp. 16–25. 
  7. ^ Keys, A. (1952). "The Cholesterol Problem". Voeding (13): 539–555. 
  8. ^ a b Ancel Keys (ed), Seven Countries: A multivariate analysis of death and coronary heart disease, 1980. Cambridge, Mass.: Harvard University Press. ISBN 0-674-80237-3.
  9. ^ D. Kromhout, "Serum cholesterol in cross-cultural perspective: The Seven Countries Study" Acta Cardiological 54:3:155-8 (June 1999)
  10. ^ A. Menotti, M. Lanti, D. Kromhout, H. Blackburn, D. Jacobs, A. Nissinen, A. Dontas, A. Kafatos, S. Nedeljkovic, H. Adachi, "Homogeneity in the relationship of serum cholesterol to coronary deaths across different cultures: 40-year follow-up of the Seven Countries Study" European Journal of Cardiovascular Prevention and Rehabilitation 15:6:719-25 (Dec 2008)
  11. ^ D.B. Panagiotakos, C. Pitsavos, E. Polychronopoulos, C. Chrysohoou, A. Menotti, A. Dontas, C. Stefanadis, "Total serum cholesterol and body mass index in relation to 40-year cancer mortality (the Corfu cohort of the seven countries study)" Cancer Epidemiology, Biomarkers and Prevention 14:7:1797-801 (July 2005)
  12. ^ van den Hoogen PC, Feskens EJ, Nagelkerke NJ, Menotti A, Nissinen A, Kromhout D (Jan 2000). "The relation between blood pressure and mortality due to coronary heart disease among men in different parts of the world". N Engl J Med. 342 (1): 1–8. doi:10.1056/nejm200001063420101. 
  13. ^ Menotti A, Jacobs DR Jr, Blackburn H, Kromhout D, Nissinen A, Nedeljkovic S, Buzina R, Mohacek I, Seccareccia F, Giampaoli S, Dontas A, Aravanis C, Toshima H (Mar 1996). "Twenty-five-year prediction of stroke deaths in the seven countries study: the role of blood pressure and its changes". Stroke. 27 (3): 381–7. doi:10.1161/01.str.27.3.381. 
  14. ^ a b Menotti A, Keys A, Aravanis C, Blackburn H, Dontas A, Fidanza F, Karvonen MJ, Kromhout D, Nedeljkovic S, Nissinen A; et al. (Jun 1989). "Seven Countries Study. First 20-year mortality data in 12 cohorts of six countries". Ann Med. 21 (3): 175–9. doi:10.3109/07853898909149929. 
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  33. ^ Keys A, Aravanis C, Blackburn H, Van Buchem FS, Buzina R, Djordjevic BS, Fidanza F, Karvonen MJ, Menotti A, Puddu V, Taylor HL (Apr 1972). "Probability of middle-aged men developing coronary heart disease in five years". Circulation. 45 (4): 815–28. doi:10.1161/01.cir.45.4.815. 
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References[edit]

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External links[edit]