Re: Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73)
To the Editors
The recent paper by Ramsden et al. (1) on the Minnesota coronary heart disease prevention trial is an interesting historical footnote that has no relevance to current dietary recommendations. We have known for many years that the classical diet-heart is incomplete, including recognition of the importance of both N-3 fatty acids and N-6 dietary fatty acids, the roles of different cholesterol fractions, and the many other pathways that connect diet with heart disease (2).
The diet used in the Minnesota trial was never consumed by any appreciable number of Americans and is not recommended by the American Heart Association (AHA) or any group. The level of linoleic acid was well above the range recommended by the AHA; to get to this level the investigators created fake meat, cheese, and milk by removing the natural fats as much as possible and replacing these with corn oil. Whatever small amounts of N-3 fatty were present would have been removed. They also created a special corn oil margarine that was lower in trans fat than the standard margarine, but we now know that the most dangerous types of trans fat (18:2 trans isomers) are likely to be higher in these lightly hydrogenated products than in the more heavily hydrogenated forms (3).
Even in its time, the Minnesota trial, conducted among patients in mental hospitals, was a major failure due to the massive dropouts and very short duration on the assigned diets. This trial was the victim of the deinstitutionalization of patients in these hospitals that occurred in the 1960’s and 70’s. The original authors enrolled 9423 assuming that at least three years would be needed to detect a benefit of the diet. At that time patients hospitalized with chronic mental illness seemed to be a good population to study because they were a “captive audience” that could be kept on assigned diets for many years. However, largely because of patients being discharged, 75% of the subjects were lost within the first year, and only 17% of those enrolled remained in the study at two years. Many fewer would have stayed a full three years, which is still a short time to study the effects of diet on atherosclerosis. The study was clearly a failure for reasons beyond the control of the investigators, and it adds very minimal information, if any, about the long term effects of diet on risk of heart disease.
The main results of this study were published by Frantz et al. in 1989 (4), with all of the above limitations, and reported no benefit on myocardial infarctions, sudden deaths, or all-cause mortality. Any implications that the authors failed to report their findings appropriately is simply incorrect, and the present BMJ paper adds no new data to this conclusion. Ramsden et al. show a figure describing no effect on total mortality, which was reported by Frantz et al., and would be expected if there is no effect on risk of heart disease. The causes of deaths in the BMJ paper are not known, which makes this endpoint particularly uninformative, especially in these hospitalized patients who likely had complex conditions. A small amount of new but incomplete data on autopsies was included in the BMJ report. However, the average follow up before death was less than one year from baseline, making it unlikely that any effect of diet on atherosclerosis would be seen in gross autopsy findings.
The authors include a meta-analysis of published data examining mortality from coronary heart disease. In addition to the major limitations of the Minnesota and other studies included, the statistical power was low for cardiac mortality and the confidence interval includes a potential important benefit. Importantly, the authors fail to mention that they earlier reported a benefit for incidence of coronary heart disease in a meta-analysis of randomized trials of trials in which saturated fat was replaced by a vegetable oils high in linoleic acid with a small amount of N-3 fatty acids, usually as soybean oil (5). Notably, N-3 fatty acids can be obtained from seafood as well as plant oils, but seafood intake was likely to be low in Minnesota in that period of time.
Overall, this report adds no useful new information and is irrelevant to current dietary recommendations that emphasize overall dietary patterns and replacing saturated fat with polyunsaturated fat, including sources of both N-3 and N-6 fatty acids. Many lines of evidence support this conclusion, including beneficial effects on blood lipids (6), and summaries of prospective cohort studies (7) and randomized trials (8, 5), including the meta-analysis previously published by Ramsden and others. Notably, since the 1960’s the US diet has changed in this direction; intake of linoleic acid has approximately doubled, and this has corresponded to a greater than 60% decline in coronary heart disease mortality and a major increase in life expectency. Although multiple factors have contributed to this decline, none of the other factors can explain this huge improvement in health, and the replacement of saturated fat with polyunsaturated fat (both N-6 and N-3) is almost certainly a major, probably most important, factor. Reversing these changes would almost certainly result in great harm.
Although we have a high level of evidence that the above direction of dietary change has been beneficial, more research is desirable to determine optimal intakes of different types and sources of dietary fat and their effects on all major health outcomes.
Sincerely,
Walter Willett, MD DrPH
Harvard University
1. Ramsden CE, Zamaora D, Majchrzak-Hong S, et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ 2016;352:i1246
2. Willett W. Nutritional Epidemiology, Oxford University Press, 2012
3. Sun Q, Ma J, Campos H, Hankinson SE, Manson JE, Stampfer MJ, Rexrode KM, Willett WC, Hu FB. A prospective study of trans fatty acids in erythrocytes and risk of coronary heart disease. Circulation 2007;115:1858-65.
4. Frantz ID Jr., Dawson EA, Ashman PL, et al. Test of effect of lipid lowering by diet on cardiovascular risk. The Minnesota Coronary Survey. Arteriosclerosis 1989;9:129-35.
5. Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, Ringel A, Davis JM, Hibbeln JR. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ. 2013 Feb 4;346:e8707
6. Mensink, R.P., et al., Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr, 2003. 77(5): p. 1146-55
7. Farvid MS, Ding M, Pan A, et al. Dietary linoleic acid and risk of coronary heart disease:a systematic review and meta-analysis of prospective cohort studies. Circulation 2014;130:1568-78.
Rapid Response:
Re: Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73)
To the Editors
The recent paper by Ramsden et al. (1) on the Minnesota coronary heart disease prevention trial is an interesting historical footnote that has no relevance to current dietary recommendations. We have known for many years that the classical diet-heart is incomplete, including recognition of the importance of both N-3 fatty acids and N-6 dietary fatty acids, the roles of different cholesterol fractions, and the many other pathways that connect diet with heart disease (2).
The diet used in the Minnesota trial was never consumed by any appreciable number of Americans and is not recommended by the American Heart Association (AHA) or any group. The level of linoleic acid was well above the range recommended by the AHA; to get to this level the investigators created fake meat, cheese, and milk by removing the natural fats as much as possible and replacing these with corn oil. Whatever small amounts of N-3 fatty were present would have been removed. They also created a special corn oil margarine that was lower in trans fat than the standard margarine, but we now know that the most dangerous types of trans fat (18:2 trans isomers) are likely to be higher in these lightly hydrogenated products than in the more heavily hydrogenated forms (3).
Even in its time, the Minnesota trial, conducted among patients in mental hospitals, was a major failure due to the massive dropouts and very short duration on the assigned diets. This trial was the victim of the deinstitutionalization of patients in these hospitals that occurred in the 1960’s and 70’s. The original authors enrolled 9423 assuming that at least three years would be needed to detect a benefit of the diet. At that time patients hospitalized with chronic mental illness seemed to be a good population to study because they were a “captive audience” that could be kept on assigned diets for many years. However, largely because of patients being discharged, 75% of the subjects were lost within the first year, and only 17% of those enrolled remained in the study at two years. Many fewer would have stayed a full three years, which is still a short time to study the effects of diet on atherosclerosis. The study was clearly a failure for reasons beyond the control of the investigators, and it adds very minimal information, if any, about the long term effects of diet on risk of heart disease.
The main results of this study were published by Frantz et al. in 1989 (4), with all of the above limitations, and reported no benefit on myocardial infarctions, sudden deaths, or all-cause mortality. Any implications that the authors failed to report their findings appropriately is simply incorrect, and the present BMJ paper adds no new data to this conclusion. Ramsden et al. show a figure describing no effect on total mortality, which was reported by Frantz et al., and would be expected if there is no effect on risk of heart disease. The causes of deaths in the BMJ paper are not known, which makes this endpoint particularly uninformative, especially in these hospitalized patients who likely had complex conditions. A small amount of new but incomplete data on autopsies was included in the BMJ report. However, the average follow up before death was less than one year from baseline, making it unlikely that any effect of diet on atherosclerosis would be seen in gross autopsy findings.
The authors include a meta-analysis of published data examining mortality from coronary heart disease. In addition to the major limitations of the Minnesota and other studies included, the statistical power was low for cardiac mortality and the confidence interval includes a potential important benefit. Importantly, the authors fail to mention that they earlier reported a benefit for incidence of coronary heart disease in a meta-analysis of randomized trials of trials in which saturated fat was replaced by a vegetable oils high in linoleic acid with a small amount of N-3 fatty acids, usually as soybean oil (5). Notably, N-3 fatty acids can be obtained from seafood as well as plant oils, but seafood intake was likely to be low in Minnesota in that period of time.
Overall, this report adds no useful new information and is irrelevant to current dietary recommendations that emphasize overall dietary patterns and replacing saturated fat with polyunsaturated fat, including sources of both N-3 and N-6 fatty acids. Many lines of evidence support this conclusion, including beneficial effects on blood lipids (6), and summaries of prospective cohort studies (7) and randomized trials (8, 5), including the meta-analysis previously published by Ramsden and others. Notably, since the 1960’s the US diet has changed in this direction; intake of linoleic acid has approximately doubled, and this has corresponded to a greater than 60% decline in coronary heart disease mortality and a major increase in life expectency. Although multiple factors have contributed to this decline, none of the other factors can explain this huge improvement in health, and the replacement of saturated fat with polyunsaturated fat (both N-6 and N-3) is almost certainly a major, probably most important, factor. Reversing these changes would almost certainly result in great harm.
Although we have a high level of evidence that the above direction of dietary change has been beneficial, more research is desirable to determine optimal intakes of different types and sources of dietary fat and their effects on all major health outcomes.
Sincerely,
Walter Willett, MD DrPH
Harvard University
1. Ramsden CE, Zamaora D, Majchrzak-Hong S, et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ 2016;352:i1246
2. Willett W. Nutritional Epidemiology, Oxford University Press, 2012
3. Sun Q, Ma J, Campos H, Hankinson SE, Manson JE, Stampfer MJ, Rexrode KM, Willett WC, Hu FB. A prospective study of trans fatty acids in erythrocytes and risk of coronary heart disease. Circulation 2007;115:1858-65.
4. Frantz ID Jr., Dawson EA, Ashman PL, et al. Test of effect of lipid lowering by diet on cardiovascular risk. The Minnesota Coronary Survey. Arteriosclerosis 1989;9:129-35.
5. Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, Ringel A, Davis JM, Hibbeln JR. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ. 2013 Feb 4;346:e8707
6. Mensink, R.P., et al., Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr, 2003. 77(5): p. 1146-55
7. Farvid MS, Ding M, Pan A, et al. Dietary linoleic acid and risk of coronary heart disease:a systematic review and meta-analysis of prospective cohort studies. Circulation 2014;130:1568-78.
8. http://health.gov/dietaryguidelines/2015-scientific-report/
Competing interests: No competing interests