Seven Countries Study

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The Seven Countries Study is an epidemiological longitudinal study that was the first study to systematically examine 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. However, a degree of scientific controversy continues.


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 that he recruited into a prospective study in 1947, the first of many cohort studies eventually mounted internationally. The men were followed through 1981 and the first major report appeared in 1963 after the fifteen-year follow-up study.[1] 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. Meanwhile, 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%.[2] The Seven Countries Study has continued for more than 50 years. The above reference summarizes its principal findings.

Major findings[edit]

The Seven Countries Study showed that the risk and rates of heart attack and stroke cardiovascular risk both at the population level and at the individual level was directly and independently related to the level of total serum cholesterol. It demonstrated that the association between blood cholesterol level and coronary heart disease (CHD) risk from 5 to 40 years follow-up is found consistently across different cultures. Cholesterol and obesity were associated with increased mortality from cancer.[3][4][5]

Objective data on CVD health in relation to the Mediterranean diet originated from the Seven Countries Study. 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. When investigated further, the importance of the eating pattern characterized as the Mediterranean diet became clear.[6][7][8][9][10] What exactly is meant by "Mediterranean diet" today, and its benefits, is detailed by other researches: Walter Willett of Harvard University,[11][12][13][14][15]

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 increases risk of heart disease.[16][17] 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.[18]

The Seven Countries Study, along with other important large studies, e.g. the Framingham Heart Study, Nurses' Health Study, Women's Health Initiative, confirmed not only the importance of healthy diet, but also of not being overweight or obese, and of regular exercise, in maintaining good general health. It also showed that regular exercise and dietary fibre strongly influence body fat levels [citation needed]. These and other research findings made it possible to calculate the probability of an individual developing coronary heart disease in the future.[19][20][21][22]

The Seven Countries Study demonstrated that elevated blood pressure (hypertension) increases risk of coronary heart disease and stroke. It showed that the mortality rate after a coronary heart disease event or stroke can be influenced by the level of hypertension. In several cohorts of the study, stroke deaths exceeded deaths from coronary heart disease.[23][24]

The Seven Countries Study showed that differences in overall mortality between the different regions of the world are largely accounted for by the variation in cardiovascular mortality.[25]

The Seven Countries Study confirmed 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 important studies about smoking, e.g. the Framingham Heart Study and the British Doctors Study.[26][27][28][29]

The Seven Countries Study revealed the importance of good cardiovascular health in avoiding 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]


Even before the study had begun, there had been criticism of its methods. Yerushalmy and Hilleboe pointed out that, for an earlier study demonstrating this association, 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.[31] They also pointed out that Keys was studying a "tenuous association" rather than any possible proof of causation. Moreover, there were other factors that could have been considered. For example sugar consumption was not studied, yet might have shown a stronger correlation, and been a better candidate for dietary intervention than fat. It should be noted that the most healthy people, in Crete and Corfu, ate less than 15 pounds of sugar per person per year, and in Japan, less than 40. This can be contrasted with 60 pounds of sugar per person in England and Wales during sugar rationing in World War II. [32]

Controversy continues about the study itself, 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.[33][34] A meta-analysis in 2014 finds that "current evidence does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total saturated fats".[35] However, this meta-study has also met with controversy, with Walter Willett of Harvard aggressively continuing to defend the older negative view of saturated fat.[36]


  1. ^ Keys A, Taylor HL, Blackburn H, Brozek J, Anderson JT, Simonson E., "Coronary Heart Disease among Minnesota Business and Professional Men Followed Fifteen Years", Circulation 28:381-95 (Sept 1963).
  2. ^ Ancel Keys (ed), Seven Countries: A multivariate analysis of death and coronary heart disease, 1980. ISBN 0-674-80237-3.
  3. ^ D. Kromhout, "Serum cholesterol in cross-cultural perspective: The Seven Countries Study" Acta Cardiological 54:3:155-8 (June 1999)
  4. ^ 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)
  5. ^ 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)
  6. ^ Epidemiological studies related to coronary heart disease: characteristics of men aged 40-59 in seven countries. Keys A, Aravanis C, Blackburn HW, Van Buchem FS, Buzina R, Djordjević BD, Dontas AS, Fidanza F, Karvonen MJ, Kimura N, Lekos D, Monti M, Puddu V, Taylor HL. Acta Med Scand Suppl. 1966;460:1-392.
  7. ^ Coronary heart disease in seven countries. Keys A (Ed). Circulation. 1970 Apr;41(4 Suppl):I 1-200.
  8. ^ The seven countries study: 2,289 deaths in 15 years. Keys A, Menotti A, Aravanis C, Blackburn H, Djordevic BS, Buzina R, Dontas AS, Fidanza F, Karvonen MJ, Kimura N, et al. Prev Med. 1984 Mar;13(2):141-54.
  9. ^ Seven Countries Study. First 20-year mortality data in 12 cohorts of six countries. Menotti A, Keys A, Aravanis C, Blackburn H, Dontas A, Fidanza F, Karvonen MJ, Kromhout D, Nedeljkovic S, Nissinen A, et al. Ann Med. 1989 Jun;21(3):175-9.
  10. ^ Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. Knoops KT, de Groot LC, Kromhout D, Perrin AE, Moreiras-Varela O, Menotti A, van Staveren WA. JAMA. 2004 Sep 22;292(12):1433-9.
  11. ^ Health implications of Mediterranean diets in light of contemporary knowledge. 1. Plant foods and dairy products. Kushi LH, Lenart EB, Willett WC. Am J Clin Nutr. 1995 Jun;61(6 Suppl):1407S-1415S.
  12. ^ Health implications of Mediterranean diets in light of contemporary knowledge. 2. Meat, wine, fats, and oils. Kushi LH, Lenart EB, Willett WC. Am J Clin Nutr. 1995 Jun;61(6 Suppl):1416S-1427S.
  13. ^ The Mediterranean diet: science and practice. Willett WC. Public Health Nutr. 2006 Feb;9(1A):105-10.
  14. ^ Mediterranean diet and incidence of and mortality from coronary heart disease and stroke in women. Fung TT, Rexrode KM, Mantzoros CS, Manson JE, Willett WC, Hu FB. Circulation. 2009 Mar 3;119(8):1093-100.
  15. ^ Eat, Drink, and Be Healthy: The Harvard Medical School Guide to Healthy Eating. By Walter C. Willett. Free Press. 2005. ISBN 0-7432-6642-0
  16. ^ Heart disease risk-factor status and dietary changes in the Cretan population over the past 30 y: the Seven Countries Study. Kafatos A, Diacatou A, Voukiklaris G, Nikolakakis N, Vlachonikolis J, Kounali D, Mamalakis G, Dontas AS. Am J Clin Nutr. 1997 Jun;65(6):1882-6.
  17. ^ Inter-cohort differences in coronary heart disease mortality in the 25-year follow-up of the seven countries study. Menotti A, Keys A, Kromhout D, Blackburn H, Aravanis C, Bloemberg B, Buzina R, Dontas A, Fidanza F, Giampaoli S, et al. Eur J Epidemiol. 1993 Sep;9(5):527-36.
  18. ^ Mediterranean diet and the incidence of cardiovascular disease: A Spanish cohort. Martínez-González MA, García-López M, Bes-Rastrollo M, Toledo E, Martínez-Lapiscina EH, Delgado-Rodriguez M, Vazquez Z, Benito S, Beunza JJ. Nutr Metab Cardiovasc Dis. 2010 Jan 20.
  19. ^ Underweight and overweight in relation to mortality among men aged 40-59 and 50-69 years: the Seven Countries Study. Visscher TL, Seidell JC, Menotti A, Blackburn H, Nissinen A, Feskens EJ, Kromhout D. Am J Epidemiol. 2000 Apr 1;151(7):660-6.
  20. ^ Saturated fat, vitamin C and smoking predict long-term population all-cause mortality rates in the Seven Countries Study. Kromhout D, Bloemberg B, Feskens E, Menotti A, Nissinen A. Int J Epidemiol. 2000 Apr;29(2):260-5.
  21. ^ Physical activity and dietary fiber determine population body fat levels: the Seven Countries Study. Kromhout D, Bloemberg B, Seidell JC, Nissinen A, Menotti A. Int J Obes Relat Metab Disord. 2001 Mar;25(3):301-6.
  22. ^ Probability of middle-aged men developing coronary heart disease in five years. Keys A, Aravanis C, Blackburn H, Van Buchem FS, Buzina R, Djordjevic BS, Fidanza F, Karvonen MJ, Menotti A, Puddu V, Taylor HL. Circulation. 1972 Apr;45(4):815-28.
  23. ^ The relation between blood pressure and mortality due to coronary heart disease among men in different parts of the world. Seven Countries Study Research Group. van den Hoogen PC, Feskens EJ, Nagelkerke NJ, Menotti A, Nissinen A, Kromhout D. N Engl J Med. 2000 Jan 6;342(1):1-8.
  24. ^ Twenty-five-year prediction of stroke deaths in the seven countries study: the role of blood pressure and its changes. 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. Stroke. 1996 Mar;27(3):381-7.
  25. ^ Seven Countries Study. First 20-year mortality data in 12 cohorts of six countries. Menotti A, Keys A, Aravanis C, Blackburn H, Dontas A, Fidanza F, Karvonen MJ, Kromhout D, Nedeljkovic S, Nissinen A, et al. Ann Med. 1989 Jun;21(3):175-9.
  26. ^ The relationship of age, blood pressure, serum cholesterol and smoking habits with the risk of typical and atypical coronary heart disease death in the European cohorts of the Seven Countries Study. Menotti A, Lanti M, Nedeljkovic S, Nissinen A, Kafatos A, Kromhout D. Int J Cardiol. 2006 Jan 13;106(2):157-63.
  27. ^ Cigarette smoking and mortality risk: twenty-five-year follow-up of the Seven Countries Study. Jacobs DR Jr, Adachi H, Mulder I, Kromhout D, Menotti A, Nissinen A, Blackburn H. Arch Intern Med. 1999 Apr 12;159(7):733-40.
  28. ^ Mortality in relation to smoking: 50 years' observations on male British doctors. Doll R, Peto R, Boreham J, Sutherland I. BMJ. 2004 Jun 26;328(7455):1519.
  29. ^ The health risks of smoking. The Framingham Study: 34 years of follow-up. Freund KM, Belanger AJ, D'Agostino RB, Kannel WB. Ann Epidemiol. 1993 Jul;3(4):417-24.
  30. ^ Cardiovascular risk factors and dementia mortality: 40 years of follow-up in the Seven Countries Study. Alonso A, Jacobs DR Jr, Menotti A, Nissinen A, Dontas A, Kafatos A, Kromhout D. J Neurol Sci. 2009 May 15;280(1-2):79-83.
  31. ^ Yerushalmy J, Hilleboe HE. Fat in the diet and mortality from heart disease. A methodologic note. NY State J Med 1957;57:2343–54.
  32. ^
  33. ^ Taubes, Gary. Good Calories, Bad Calories: Fats, Carbs, and the Controversial Science of Diet and Health. Anchor, 2008.
  34. ^ Uffe Ravnskov. A hypothesis out-of-date: The diet–heart idea. Journal of Clinical Epidemiology 55 (2002) 1057–1063. PII: S0895-4356(02)00504-8. accessed 18 March 2014
  35. ^ Association of Dietary, Circulating, and Supplement Fatty Acids With Coronary Risk: A Systematic Review and Meta-analysis. Rajiv Chowdhury, MD, PhD; Samantha Warnakula, MPhil; Setor Kunutsor, MD, MSt; Francesca Crowe, PhD; Heather A. Ward, PhD; Laura Johnson, PhD; Oscar H. Franco, MD, PhD; Adam S. Butterworth, PhD; Nita G. Forouhi, MRCP, PhD; Simon G. Thompson, FMedSci; Kay-Tee Khaw, FMedSci; Dariush Mozaffarian, MD, DrPH; John Danesh, FRCP*; and Emanuele Di Angelantonio, MD, PhD. Annals of Internal Medicine. 2014;160(6):398-406-406. doi:10.7326/M13-1788
  36. ^ "Scientists Fix Errors in Controversial Paper About Saturated Fats"

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