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; 346 doi: http://dx.doi.org/10.1136/bmj.e8707 (Published 5 February 2013)
Cite this as: BMJ 2013;346:e8707

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Dear Sir,

We thank Hornstra et al. for their interest in our manuscript [1]. However, their letter includes important errors and misrepresentations, which distract from—but do not alter—the central finding of the Sydney Diet Heart Study. The intervention group, which substituted linoleic acid (n-6 LA) rich liquid safflower oil and safflower polyunsaturated margarine in place of animal fats and common margarines, had increased risk of death from all-causes, cardiovascular disease, and coronary heart disease, despite a significant reduction in blood cholesterol.

Below, we address the most salient errors in their letter. Further, we invite any reader seeking the broader context that is needed to evaluate the results and the limitations of the Sydney Diet Heart Study to read our detailed manuscript [1], web appendices [2], and a previous author reply [3].

Incorrect representation of the numbers of deaths

Hornstra et al. incorrectly assert that there were “63 all cause mortality cases and just 7 additional deaths in the intervention as compared to the control group”. In fact, there were 67 total deaths, 39 of 221 randomized to the n-6 LA intervention group versus 28 of 237 randomized to the control group (a difference of 11). These are the same numbers reported in the 1978 publication [4]. Using standard survival analysis methodology to compare mortality rates between groups on an intention-to-treat basis, we found that the intervention group had increased all cause mortality (17.6% v 11.8%; hazard ratio 1.62 (95% confidence interval 1.00 to 2.64); P=0.05).

Importantly, we were also able to recover and analyze critical outcomes (mortality from cardiovascular disease and coronary heart disease), which were previously unpublished. The intervention group had increased cardiovascular mortality (17.2% v 11.0%; 1.70 (1.03 to 2.80); P=0.04), and mortality from coronary heart disease (16.3% v 10.1%; 1.74 (1.04 to 2.92); P=0.04). These adverse outcomes, which show that subjects randomized to the LA intervention fared worse than subjects randomized to the control group, are the main findings of the trial.

Mischaracterizing limitations of a randomized controlled trial

The Sydney Diet Heart Study was a randomized controlled trial (RCT), not an observational study. All non-dietary components were designed to be equivalent in both groups, allowing for assessment of the effects of the dietary intervention. As noted in our manuscript, both groups made healthy lifestyle modifications (e.g. smoking reduction), probably from the personal reassessment that accompanies a coronary event. This is consistent with other secondary prevention coronary heart disease trials. Since both groups were well balanced at baseline, this RCT design evaluates the effects of the dietary intervention.

As Hornstra et al. noted, a limitation of this RCT is that the intervention group received more intensive treatment than the control group (which had no food provision or dietary counseling). However, a resulting placebo effect would be expected improve outcomes in the intervention group (5). Therefore, the finding of higher death rates in the intervention group—opposite of the expected benefit—may actually underestimate the adverse effects of the intervention.

Mischaracterization as a ‘recalculation study’

Hornstra et al. could have benefited by reading our manuscript [1] and detailed web appendices [2] more carefully before mischaracterizing our secondary analysis as a ‘re-calculation’ study. While not all trial records could be recovered, only variables that exactly matched published data were included in our analysis. All matching variables were further verified by Dr. B. Leelarthaepin, an original study investigator and co-author on the present manuscript, in order to ensure accuracy.

The original data included baseline and longitudinal intakes of target nutrients (PUFA, SFA and PUFA to SFA ratio) calculated by the original study investigators. These nutrient variables exactly matched the baseline and follow-up nutrient intake data reported in Tables 2 and 3, respectively, in the 1978 publication [4], affirming the accuracy of these recovered original data. Some of these nutrient variables were not normally distributed. We therefore appropriately expressed the nutrients as medians (and interquartile ranges) rather than as means (and standard deviations) reported in the 1978 publication. The median baseline and composite follow-up dietary data are reported in Table 3 of our manuscript, and more detailed follow-up dietary data (for 5 years) are presented in Web Appendix Table 2. Together, our presentation of these recovered (not re-calculated) original data provide a more complete depiction of the study diets than was presented in the 1978 publication.

In addition to correcting the erroneous ‘recalculation’ claim, we would like to clarify that the original study investigators did not evaluate the association between increases in n-6 LA and mortality. At the time of the Sydney Diet Heart Study, PUFAs were regarded as a uniform molecular category with one relevant biological mechanism—the reduction in blood cholesterol. Because the original study investigators did not appreciate that individual PUFA species may have different biochemical and clinical effects, they did not attempt to estimate the effects of n-6 LA on mortality outcomes.

Conclusion

Hornstra et al. suggest that a ‘golden rule of Good Clinical Practice’ precludes not only evaluation of missing clinical trial data, but also re-evaluation of completed trials in light of scientific progress. We would like to direct Hornstra et al. to the BMJ theme emphasizing the importance of recovering missing clinical trial data to correct distortions in the evidence-base [6,7]. Our manuscript presents critical—but previously missing—outcomes from a randomized controlled trial, and further evaluates trial data in the context of current understanding of polyunsaturated fatty acids.

Recovery and analysis of these missing data has filled a critical gap in the published literature archive. For the first time, scientists and policymakers have access to cardiovascular and coronary heart disease outcomes from all known randomized controlled dietary trials testing the cardiovascular effects of replacing saturated fats with n-6 linoleic acid, or a mixture of n-6 and n-3 polyunsaturated fatty acids.

References
1. Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, et al. 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;346:e8707.

2. Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, et al. BMJ 2013;346:e8707. Web appendices/Supplementary material, pages 1-20.
3. Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, et al.
Author reply: Can vegetable oil processing help explain the increased cardiovascular mortality in the Sydney Diet Heart Study? (http://www.bmj.com/content/346/bmj.e8707/rr/631590)
4. Woodhill JM, Palmer AJ, Leelarthaepin B, McGilchrist C, Blacket RB. Low fat, low cholesterol diet in secondary prevention of coronary heart disease. Adv Exp Med Biol 1978;109:317-30.
5. Bienenfeld L, Frishman W, Glasser SP. The placebo effect in cardiovascular disease.
Am Heart J. 1996; 132:1207-21
6. Lehman R, Loder E. Missing clinical trial data. BMJ 2012; 344 BMJ 2012;344:d8158
7. Loder E. A theme issue in 2011 on unpublished evidence. BMJ 2011;342:d2627.

Competing interests: None declared

Christopher E Ramsden, Clinical Investigator

Christopher E Ramsden, Daisy Zamora, Boonseng Leelarthaepin, Sharon F Majchrzak-Hong, Keturah R Faurot, Chirayath M Suchindran, John M Davis, Joseph R Hibbeln

US National Institutes of Health, Bethesda, MD, 20892

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Epidemiological studies indicate that high w-6 and low w-3 fatty acids in the diet may have adverse effects on cardiovascular diseases (CVDs). However, a low w-6/w-3 ratio diet by increasing w-3 and by decreasing w-6 fatty acid in the Paleolithic style diet can cause significant decline in cardiovascular and all cause mortality.

A randomized, single blind, controlled trial was carried out on 406 patients with acute coronary syndromes (ACS) diagnosed following WHO criteria. An experimental intervention group received Paleolithic style diet characterized by fruits, vegetables, whole grains, almonds and walnuts and the control group fat modified according to the National Cholesterol Education Program Step 1 (prudent) diet. Main outcome measures were compliance with experimental diets at one year and all cause mortality and its association with w-6/w-3 fatty acid ratio after a follow up of two years. These data have not been reported in earlier publications.

The experimental group received significantly greater amount of fruits, vegetables and whole grains, nuts and mustard oil and lower amount of refined bread, biscuits and sugar and butter and clarified butter compared to control diet group at one year of follow up. Total adherence score to Paleolithic style diet and prudent diet were significant in both the groups. Omega-6/Omega-3 fatty acid ratio of the diet which was much higher before entry to the study (32.5±3.3), was brought down to significantly lower content in the Paleolithic style diet group A (n = 204, compared to control group diet B (n = 202) at entry to the study ( 3.5± 0.76 vs. 24.0± 2.4 KJ/day, p<0.001). The fatty acid ratio remained significantly much lower in the experimental group compared to control group after one year of follow up (4.4±0.56 vs. 22.3±2.1,KJ/day, p<0.001). Total mortality was 14.7% in the Paleolithic style diet group and 25.2% in the control group, after a follow up of two years. The association w-6/w-3 ratio of fatty acids with mortality showed a gradient in both the groups independently, as well as among total number of deaths. A lower w-6/w-3 ratio of fatty acids from 1-10 was associated with a significantly lower mortality whereas increase in w-6/w-3 fatty acid ratio to more than 10 was associated with an increasing trend in mortality; 1.7% at ratio less than 5 and 19.9% at ratio 30.

A Paleolithic style diet characterized with fruits, vegetables, nuts, whole grains and mustard oil with low w-6/w-3 fatty acids ratio <5, is more effective in causing significant decline in cardiovascular and all cause mortality compared to prudent diet in the secondary prevention of coronary artery disease. The association of mortality was consistent with increase in w-6/w-3 fatty acid ratio in the diets in both the groups and the trends were highly significant.We congratulate the authors of this study because we have the same views.
World Heart Jour 2012;4:71-84

Competing interests: None declared

Ram B Singh, Cardiologist

Halberg Hospital, Civil Lines, Moradabad, India

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Gerard Hornstra PhD,
Professor of Experimental Nutrition (Rtd), Maastricht University,
Maastricht, The Netherlands
and
Connie Diekman MEd, RD, FADA,
Director of University Nutrition, Washington University in St Louis,
Academy of Nutrition and Dietetics Past President

on behalf of the International Expert Movement on Health Significance of Fat Quality of the Diet, a working group under the auspices of the International Union of Nutritional Sciences

Dear Sir,
We congratulate Christopher Ramsden and colleagues on an elegant piece of ‘scientific archeology’, in which they recalculated and re-evaluated the results of the 40-year-old Sydney Diet Heart Study (SDHS) 1 and concluded that ‘substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease’ 2.

In fact, their findings confirm the original SDHS results, that excess consumption of linoleic acid (LA) to replace saturated fatty acids (SAFA) in the diet of male coronary heart disease patients was associated with reduced survival after 2-7 years of follow-up. Unfortunately, the participants were not blinded to the treatment, because the intervention group received special instructions, oils, and margarines to increase their polyunsaturated fatty acid (PUFA) intake and to reduce SAFA consumption, whereas the control group did not receive a similar treatment with control products. In addition, the trial was confounded by multiple changes within both groups, not only in diet (see below) but also in lifestyle (e.g. sharp decrease in cigarette smoking, considerable reductions in caloric in take, body weight, and alcohol consumption, and substantial increase in physical exercise). These lifestyle changes commenced after the cardiovascular event, continued during the trial, and could not be corrected for.

In the original SDHS paper 1, the authors clearly stated that, based on multivariate analyses, ‘none of the dietary factors were significantly related to survival’. In contrast, Ramsden and colleagues, who applied different statistics, held the high linoleic acid intake fully responsible for the negative outcome observed. Results of Ramsden’s diet recalculations differed only slightly from the original dietary composition data, which is quite an achievement, since post hoc diet calculations are acknowledged to be extremely difficult and can be rather inaccurate 3. Because of these relatively small dietary discrepancies, the different statistical methods applied must have been crucial to the dissimilarity between both outcomes.

Ramsden’s approach inevitably needed to violate the golden rule of Good Clinical Practice, that any study evaluation plan needs to be part of the study design and should, therefore, precede study execution. However, Ramsden and colleagues should have explained why they decided to use different statistics. Moreover, it would have been illustrative and more convincing if the reason(s) for the different outcomes had been described, and if results had been presented of cross-validation studies (evaluation of original data with present statistics, and assessment of recalculated data with original statistics).

Inclusion of the present results in Ramsden’s earlier meta-analysis of linoleic acid-specific saturated fat replacements 4 strengthened the initial trend for a cardiovascular risk increase of an excessively high LA intake. The hazard ratio increased from about 1.1 to 1.3, but possibly because of the limited size of the SDHS (63 all cause mortality cases and just 7 additional deaths in the intervention as compared to the control group), it still did not reach significance.
We doubt whether this inclusion is justified, however, because the SDHS, originally planned as a dietary replacement trial, turned out to be flawed by multifactorial changes, as mentioned above. In addition, certain interpretations of the re-evaluation results deserve some scrutiny. Thus, although the dietary intervention intended to be an LA-specific SAFA replacement, it also significantly reduced the consumption of monounsaturated fatty acids, the impact of which on cardiovascular risk is not clear as yet 5. In addition, the authors neither excluded, nor corrected for, the possibility that the SDHS intervention reduced the omega-3 PUFA intake as a result of replacing the habitual cooking oils. Further, a possible increase in the consumption of industrial trans fatty acids by the intervention group was not accounted for, whereas at that time high PUFA margarines contained significant amounts (as high as 15 - 20%) of these cardiovascular risk increasing fatty acids (P. Clifton, W. Shrapnel, http://www.smc.org.au/2013/02/round-up-dietary-fats-and-heart-disease-bm... , and P. Zock, personal communication). These unintentional further changes may have affected mortality in the intervention group independent from an assumed LA effect.

Considering these issues, we believe that the conclusion of Ramsden and colleagues that their findings ‘could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats’ is not justified. This conclusion is incompatible with Ramsden’s earlier 4 and present 2 meta-analyses and with the meta-analysis of Mozaffarian and colleagues 6, all demonstrating that replacing SAFA (and industrial trans) with PUFA (being a mix of 15-20 en% LA and some omega-3 PUFA) significantly reduces the risk of coronary heart disease.

Nonetheless it would be unwise to ignore the present outcome of Ramsden’s recalculation study, since it adds to the growing concern about the safety of an unlimited increase in LA consumption. Other contributions to the emerging LA skepticism are the well-documented reduction of the omega-3 long-chain PUFA status by dietary LA 7 8, its possible effects on early human development 9, its controversial pro-inflammatory potential 10 11, and its alleged contributing role in the present obesity epidemic 12 13.

Finally, Ramsden and colleagues correctly stated that any potential adverse effect of linoleic acid from 8.5 (not 6, as mentioned in their paper) to 15 %, as possibly observed in the SDHS cohort, does not necessarily apply to lower LA intakes. Since the maximum recommended LA intake for the prevention of cardiovascular disease is about 10 % 14, WHO recommendations maximize LA intake to 9 % 15, and LA intake in most countries is between 3 and 7 % 16, we believe that Ramsden’s recalculation study need not affect current LA intake recommendations. It also does not mitigate the beneficial effect of replacing dietary saturated for polyunsaturated fats to reduce cardiovascular risk.

References

1. Woodhill JM, Palmer AJ, Leelarthaepin B, McGilchrist C, Blacket RB. Low fat, low cholesterol diet in secondary prevention of coronary heart disease. Adv Exp Med Biol 1978;109:317-30.
2. Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, et al. 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;346:e8707.
3. Nettleton JA, Koletzko B, Hornstra G. ISSFAL 2010 Dinner Debate: Healthy Fats for Healthy Hearts - Annotated Report of a Scientific Discussion. Ann Nutr Metab 2011;58(1):59-65.
4. Ramsden CE, Hibbeln JR, Majchrzak SF, Davis JM. n-6 Fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials. Br J Nutr 2010;104(11):1586-600.
5. Jakobsen MU, O'Reilly EJ, Heitmann BL, Pereira MA, Balter K, Fraser GE, et al. Major types of dietary fat and risk of coronary heart disease: a pooled analysis of 11 cohort studies. Am J Clin Nutr 2009;89(5):1425-32.
6. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. PLoS Med 2010;7(3):e1000252.
7. Rump P, Hornstra G. The n-3 and n-6 polyunsaturated fatty acid composition of plasma phospholipids in pregnant women and their infants. relationship with maternal linoleic acid intake. Clin Chem Lab Med 2002;40(1):32-9.
8. Liou YA, King DJ, Zibrik D, Innis SM. Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men. J Nutr 2007;137(4):945-52.
9. Hornstra G. Essential fatty acids in mothers and their neonates. Am J Clin Nutr 2000;71(5 Suppl):1262S-9S.
10. Fritsche KL. Too much linoleic acid promotes inflammation-doesn't it? Prostaglandins Leukot Essent Fatty Acids 2008;79(3-5):173-5.
11. Bjermo H, Iggman D, Kullberg J, Dahlman I, Johansson L, Persson L, et al. Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial. Am J Clin Nutr 2012;95(5):1003-12.
12. Ailhaud G, Massiera F, Weill P, Legrand P, Alessandri JM, Guesnet P. Temporal changes in dietary fats: role of n-6 polyunsaturated fatty acids in excessive adipose tissue development and relationship to obesity. Prog Lipid Res 2006;45(3):203-36.
13. Moon RJ, Harvey NC, Robinson SM, Ntani G, Davies JH, Inskip HM, et al. Maternal Plasma Polyunsaturated Fatty Acid Status in Late Pregnancy Is Associated with Offspring Body Composition in Childhood. J Clin Endocrinol Metab 2013;98(1):299-307.
14. Kris-Etherton PM, Innis S, Ammerican Dietetic A, Dietitians of C. Position of the American Dietetic Association and Dietitians of Canada: dietary fatty acids. J Am Diet Assoc 2007;107(9):1599-611.
15. WHO/FAO. Diet, nutrition and the prevention of chronic diseases. World Health Organ Tech Rep Ser 2003;916:i-viii, 1-149, backcover.
16. Elmadfa I, Kornsteiner M. Dietary fat intake--a global perspective. Ann Nutr Metab 2009;54 Suppl 1:8-14.

Competing interests: “The International Expert Movement (IEM) is a group of experts committed to improving the fat quality of the diet of everyone. IEM’s activities are funded by an unrestricted educational grant from Unilever N.V. under the auspices of the International Union of Nutritional Sciences”. www.theiem.org <http://www.theiem.org>

Gerard Hornstra, Prof. of Experimental Nutrition

Connie Diekman

Maastricht University (Retired), Brikkenoven 14, 6247BG Gronsveld, the Netherlands

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Can vegetable oil processing help explain the increased cardiovascular mortality in the Sydney Diet Heart Study?

We appreciate Dr. Gutierrez’s interest in our manuscript “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” 1, where we reported that: (1) patients randomized to the omega-6 linoleic acid (n-6 LA) intervention group had increased cardiovascular (CVD) mortality, and (2) the magnitude of increase in n-6 LA intake among this intervention group was associated with higher risk of CVD mortality. We extensively discussed potential limitations, including the possibility that trans fat intakes may have been modified, as noted by Dr. Gutierrez. However, we also noted that the sum of changes in both groups likely produced minimal between-group differences in trans fat intakes.

In this letter we (1) provide further context to explain why trans fats are not a convincing explanation for the observed increased CVD death; and (2) expand on our proposed mechanistic model1 to include the possibility that marked between-group differences in dietary n-6 LA oxidation products may have contributed to the unfavorable effects of the intervention.

Key considerations 1 2-16:

Consumption and displacement of trans fats:

• The primary intervention fat source was liquid safflower oil, a concentrated source of n-6 LA that contains little or no trans fat. The intervention group was advised to consume 2 to 4 tablespoons per day, displacing rich sources of saturated fat, but also some important sources of trans fat including common hard margarines and shortenings. They were also advised to avoid commercial products made with common hard margarines (for example biscuits, cakes, pastries and puddings). These substitutions would have reduced trans fat in the n-6 LA intervention group compared to the control group.

• While the safflower oil soft polyunsaturated margarine that was provided to the intervention group likely contained some trans fat, it replaced not only butter, but also common table margarines, an important source of trans fat. This safflower oil polyunsaturated margarine was selected for its high n-6 LA content (about 48% of fat), nearly 3-to-1 polyunsaturated to saturated fat ratio, and cholesterol lowering properties. Although the precise amount of trans fat in this margarine was not specified, these are characteristics of soft margarines that usually contain lower amounts of trans fat compared to commercially available margarines that it would have displaced.

• Many patients in the control group also began replacing butter with commercially available polyunsaturated margarines. This substitution helps explain the substantial (but modest in comparison to the intervention group) increase in polyunsaturated fat intake in the control group. Therefore, both the intervention group and control group likely consumed some trans fat from polyunsaturated margarines.

• The intervention group also markedly reduced their intake of dietary sources of ruminant trans fats. Trans fats of ruminant origin have been associated with increased risk of CVD death in some 17, but not all 18, published observational studies.

Collectively, these observations indicate that the two groups were not likely to have substantial differences in trans fat consumption from hydrogenated sources, and the control group likely consumed higher amounts of trans fats from ruminant sources.

Putting trans fats into context with the full trial results:

• Trans fats raise serum total and low-density lipoprotein (LDL) cholesterol. Thus, the significant reduction in serum cholesterol among the n-6 LA intervention group (-13%) compared to the control group (-5.5%) in this randomized controlled trial is not consistent with the premise that increased mortality in the intervention group was due to trans fat intake.

• Dietary trans fats are predominantly 18-carbon monounsaturated fat isomers. In our analysis of changes in polyunsaturated fat in the intervention group consuming safflower oil (a concentrated source of n-6 LA), we found a robust association between the increase in polyunsaturated fats and cardiovascular death. Adjusting this analysis for monounsaturated fat (an imperfect surrogate for trans fats, as explained in our manuscript) did not noticeably alter this association between PUFA and increased mortality.

Together, these observations and other factors discussed in our manuscript indicate that trans fats are not a convincing explanation for the increased risk of death in the n-6 LA intervention group.

Dietary linoleic acid oxidation products as mediators of cardiovascular disease

We do agree in principle with Dr. Gutierrez, that processing of high n-6 LA oils (in this case safflower oil) is a plausible factor that may have contributed to the observed increased risk of cardiovascular death. The intervention group was advised to substitute liquid safflower oil (containing nearly 75% n-6 LA by weight) for saturated fats whenever possible, including when frying or otherwise cooking. At the time it was not appreciated that thermoxidation and frying of n-6 LA enriched oils generate more oxidized linoleic acid metabolites (OXLAMs) including 9- and 13-hydroperoxy-octadecadienoic acids, and 9- and 13-hydroxy-octadecadienoic acids, than fats that are predominantly saturated or monounsaturated 19-20. Lowering dietary n-6 LA reduces circulating OXLAMs in humans 21, presumably by reducing the substrate for endogenous conversion of n-6 LA to OXLAMs. However, humans also readily absorb oxidized fatty acids from dietary sources 22. Consumption of fried n-6 LA enriched oils has been shown to increase circulating OXLAMs in humans23.

In the mechanistic model proposed in our manuscript 1 24-42, we noted that OXLAMs: (1) are the most abundant oxidized fatty acids in oxidized low-density lipoprotein (oxidized LDL); (2) are enriched in the lipid-laden macrophage foam cells, vascular endothelial cells, and migrating vascular smooth muscle cells of atherosclerotic lesions; and (3) have been mechanistically linked to cardiovascular disease pathogenesis.

We previously proposed that the combination of high n-6 LA diets and an endogenous source of oxidative stress (for example smoking or heavy drinking) facilitated OXLAM-mediated atherosclerotic progression and increased CVD mortality. Consistent with this model, the link between the magnitude of increase in LA and mortality was robust in smokers and drinkers, suggesting that diets high in n-6 LA may be particularly detrimental in the context of endogenous oxidative stress.

Here, we expand on this mechanistic model to propose that exogenous OXLAMs (from heated safflower oil) may have contributed to the increased risk of CVD death in the LA intervention group. Consistent with this model, dietary OXLAMs have been shown to increase oxidation of circulating lipoproteins and to promote atherosclerotic progression in rabbits and mice 43 44.

Importantly, LA-enriched oils are ingredients in many food products that are fried or otherwise heated (for example potato chips, french fries, crackers, numerous snack foods). However, quantitative data on OXLAM content in foods and their health effects are sorely lacking.

In addition to CVD risk, OXLAMs have recently been associated with non-alcoholic steatohepatiti 45 and mechanistically linked to physical pain 46 47. Therefore, the potential implications of processing of vegetable oils enriched in n-6 LA extend beyond cardiovascular disease.

We propose that OXLAMs should be estimated in future observational studies, and measured in future dietary intervention trials. More research into the biochemical and health effects of dietary and endogenously produced OXLAMs is clearly warranted.

References

1. Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, et al. 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;346:e8707.
2. Woodhill JM, Palmer AJ, Leelarthaepin B, McGilchrist C, Blacket RB. Low fat, low cholesterol diet in secondary prevention of coronary heart disease. Adv Exp Med Biol 1978;109:317-30.
3. Palmer J, Leelarthaepin B, McGilchrist C, Blacket R. Coronary heart disease profile in Australian men and some factors influencing survival. Adv Exp Med Biol 1977;82:115-7.
4. Blacket RB, Leelarthaepin B, Palmer AJ, Woodhill JM. Coronary heart disease in young men: a study of seventy patients with a critical review of etiological factors. Aust N Z J Med 1973;3(1):39-62.
5. Blacket RB, Leelarthaepin B. Coronary disease in young men. Singapore Medical Journal 1973;14(3):344-6.
6. Blacket RB. Diet in Prevention of Heart Disease. Med J Australia 1973;1(20):969-73.
7. Palmer J, Woodhill J, Blacket R. Strict modified fat diet in coronary heart disease. The problem of nonresponders. Isr J Med Sci 1969;5(4):754-9.
8. Palmer AJ, Blacket RB, Leelarth.B. Hyperlipidemia in a Group of Coronary Subjects in Sydney. Med J Australia 1973;2(1):19-23.
9. Blacket RB, Woodhill J, Mishkel MA. Diet, hypercholesterolaemia and coronary heart disease. Med J Aust 1965;1(3):59-63.
10. Woodhill JM, Palmer, A.J., and Blacket, R.B. Dietary habits and their modification in a coronary prevention programme for Australians. . Food Technology in Australia 1969;21:264-71.
11. Woodhill JM, Bernstein L. Lowering serum cholesterol levels by dietary modification. A change in food habits, not a special diet. Med J Aust 1973;1(20):973-9.
12. Fisher M. How the 'Miracle' was cowed: margarine quotas and politics. The Australian Quarterly 1970;42(2):20-33.
13. Significant Points from the Annual Report of Marrickville Holdings. Sydney Morning Herald 19 November 1965.
14. Woodhill J. Australian dietary surveys with special reference to vitamins. International Journal of Vitamin Research 1970;40(4):520-40.
15. Mensink RP, Zock PL, Kester AD, Katan MB. 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):1146-55.
16. Chardigny JM, Malpuech-Brugere C, Dionisi F, Bauman DE, German B, Mensink RP, et al. Rationale and design of the TRANSFACT project phase I: a study to assess the effect of the two different dietary sources of trans fatty acids on cardiovascular risk factors in humans. Contemporary clinical trials 2006;27(4):364-73.
17. Laake I, Pedersen JI, Selmer R, Kirkhus B, Lindman AS, Tverdal A, et al. A prospective study of intake of trans-fatty acids from ruminant fat, partially hydrogenated vegetable oils, and marine oils and mortality from CVD. Br J Nutr 2012;108(4):743-54.
18. Bendsen NT, Christensen R, Bartels EM, Astrup A. Consumption of industrial and ruminant trans fatty acids and risk of coronary heart disease: a systematic review and meta-analysis of cohort studies. Eur J Clin Nutr 2011;65(7):773-83.
19. Marmesat S, Morales A, Velasco J, Carmen Dobarganes M. Influence of fatty acid composition on chemical changes in blends of sunflower oils during thermoxidation and frying. Food Chem 2012;135(4):2333-9.
20. Thompson L, Aust R. Lipid changes in french fries and heated oils during commercial deep frying and their nutritional and toxicological implications. Can Inst Sci Technol J. 1983;16:246-53.
21. Ramsden CE, Ringel A, Feldstein AE, Taha AY, MacIntosh BA, Hibbeln JR, et al. Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans. Prostaglandins Leukot Essent Fatty Acids 2012;87(4-5):135-41.
22. Wilson R, Lyall K, Smyth L, Fernie CE, Riemersma RA. Dietary hydroxy fatty acids are absorbed in humans: implications for the measurement of 'oxidative stress' in vivo. Free Radic Biol Med 2002;32(2):162-8.
23. Ferreiro-Vera C, Priego-Capote F, Mata-Granados JM, Luque de Castro MD. Short-term comparative study of the influence of fried edible oils intake on the metabolism of essential fatty acids in obese individuals. Food Chem 2013;136(2):576-84.
24. Folcik VA, Cathcart MK. Predominance of Esterified Hydroperoxy-Linoleic Acid in Human Monocyte-Oxidized Ldl. Journal of Lipid Research 1994;35(9):1570-82.
25. Shibata N, Toi S, Shibata T, Uchida K, Itabe H, Sawada T, et al. Immunohistochemical detection of 13(R)-hydroxyoctadecadienoic acid in atherosclerotic plaques of human carotid arteries using a novel specific antibody. Acta Histochem Cytochem 2009;42(6):197-203.
26. Harland WA, Gilbert JD, Steel G, Brooks CJW. Lipids of Human Atheroma .5. Occurrence of a New Group of Polar Sterol Esters in Various Stages of Human Atherosclerosis. Atherosclerosis 1971;13(2):239-&.
27. Carpenter KL, Taylor SE, van der Veen C, Williamson BK, Ballantine JA, Mitchinson MJ. Lipids and oxidised lipids in human atherosclerotic lesions at different stages of development. Biochim Biophys Acta 1995;1256(2):141-50.
28. Kuhn H, Belkner J, Wiesner R, Schewe T, Lankin VZ, Tikhaze AK. Structure elucidation of oxygenated lipids in human atherosclerotic lesions. Eicosanoids 1992;5(1):17-22.
29. Waddington EI, Croft KD, Sienuarine K, Latham B, Puddey IB. Fatty acid oxidation products in human atherosclerotic plaque: an analysis of clinical and histopathological correlates. Atherosclerosis 2003;167(1):111-20.
30. Vangaveti V, Baune BT, Kennedy RL. Hydroxyoctadecadienoic acids: novel regulators of macrophage differentiation and atherogenesis. Ther Adv Endocrinol Metab 2010;1(2):51-60.
31. Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 1998;93(2):229-40.
32. Xie S, Lee YF, Kim E, Chen LM, Ni J, Fang LY, et al. TR4 nuclear receptor functions as a fatty acid sensor to modulate CD36 expression and foam cell formation. Proc Natl Acad Sci U S A 2009;106(32):13353-8.
33. Wang L, Gill R, Pedersen TL, Higgins LJ, Newman JW, Rutledge JC. Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation. J Lipid Res 2009;50(2):204-13.
34. Barlic J, Zhang Y, Murphy PM. Atherogenic lipids induce adhesion of human coronary artery smooth muscle cells to macrophages by up-regulating chemokine CX3CL1 on smooth muscle cells in a TNFalpha-NFkappaB-dependent manner. J Biol Chem 2007;282(26):19167-76.
35. Natarajan R, Reddy MA, Malik KU, Fatima S, Khan BV. Signaling mechanisms of nuclear factor-kappab-mediated activation of inflammatory genes by 13-hydroperoxyoctadecadienoic acid in cultured vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2001;21(9):1408-13.
36. Kita T, Kume N, Minami M, Hayashida K, Murayama T, Sano H, et al. Role of oxidized LDL in atherosclerosis. Ann N Y Acad Sci 2001;947:199-205; discussion 05-6.
37. Yokode M, Ueyama K, Arai NH, Ueda Y, Kita T. Modification of high- and low-density lipoproteins by cigarette smoke oxidants. Ann N Y Acad Sci 1996;786:245-51.
38. Yang L, Latchoumycandane C, McMullen MR, Pratt BT, Zhang R, Papouchado BG, et al. Chronic alcohol exposure increases circulating bioactive oxidized phospholipids. J Biol Chem 2010;285(29):22211-20.
39. Esterbauer H, Jurgens G, Quehenberger O, Koller E. Autoxidation of human low density lipoprotein: loss of polyunsaturated fatty acids and vitamin E and generation of aldehydes. J Lipid Res 1987;28(5):495-509.
40. Lenz ML, Hughes H, Mitchell JR, Via DP, Guyton JR, Taylor AA, et al. Lipid hydroperoxy and hydroxy derivatives in copper-catalyzed oxidation of low density lipoprotein. J Lipid Res 1990;31(6):1043-50.
41. Brewer ER, Ashman PL, Kuba K. The Minnesota Coronary Survey: Composition of their diets, adherence, and serum lipid response. Circulation 1975;51 & 52(Supplement II):II-269.
42. Heltianu C, Robciuc A, Botez G, Musina C, Stancu C, Sima AV, et al. Modified low density lipoproteins decrease the activity and expression of lysosomal acid lipase in human endothelial and smooth muscle cells. Cell Biochem Biophys 2011;61(1):209-16.
43. Staprans I, Rapp JH, Pan XM, Hardman DA, Feingold KR. Oxidized lipids in the diet accelerate the development of fatty streaks in cholesterol-fed rabbits. Arterioscler Thromb Vasc Biol 1996;16(4):533-8.
44. Khan-Merchant N, Penumetcha M, Meilhac O, Parthasarathy S. Oxidized fatty acids promote atherosclerosis only in the presence of dietary cholesterol in low-density lipoprotein receptor knockout mice. The Journal of nutrition 2002;132(11):3256-62.
45. Feldstein AE, Lopez R, Tamimi TA, Yerian L, Chung YM, Berk M, et al. Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Lipid Res 2010;51(10):3046-54.
46. Patwardhan AM, Akopian AN, Ruparel NB, Diogenes A, Weintraub ST, Uhlson C, et al. Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents. J Clin Invest 2010;120(5):1617-26.
47. Patwardhan AM, Scotland PE, Akopian AN, Hargreaves KM. Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia. Proc Natl Acad Sci U S A 2009;106(44):18820-4.

Footnotes:
Please see the acknowledgements section of the main manuscript1. We would also like to thank Rashudy Mahomedradja and Ameer Taha for a literature review related to linoleic acid oxidation products.

Funding:
The Life Insurance Medical Research Fund of Australia and New Zealand provided a grant in support of the SDHS. The Intramural Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, and the University of North Carolina Program on Integrative Medicine (National Institutes of Health grant T-32 AT003378), supported data recovery and evaluation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Competing interests: None declared

Christopher E Ramsden, Clinical Investigator

Daisy Zamora, Boonseng Leelarthaepin, Sharon F Majchrzak-Hong, Keturah R Faurot, Chirayath M Suchindran, Amit Ringel, John M Davis, Joseph R Hibbeln

U. S. National Institutes of Health , Bethesda, MD 20892

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Dear Sir,

The study by Dr Ramsden and colleagues entitled “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” in your journal shows that substitution of omega 6 linoleic acid for saturated fat does not help in improving the cardiovascular health (1). More people are consuming commercially prepared foods and this increases the intake of transfatty acids than the food items prepared at home (2). Increased consumption of green leafy vegetables and fruits reduces the risk of coronary artery disease (3,4) Higher intake of fruits and vegetables is associated with a reduced risk of ischemic heart disease mortality(5).

A decrease in serum concentration of total cholesterol and low density lipoprotein cholesterol has been observed in men and women with increased frequency of eating (six times or more per day) (6). Shorter leukocyte telomere length (LTL) is associated with several chronic diseases. Increased processed meat intake is associated with reduction in telomere length (7). An increase in dietary fiber intake is associated with a decrease in risk of stroke (8). Leukocyte telomere length is positively associated with increase in leisure time physical activity (9).

In the study by Dr Ramsden and colleagues it would be nice to know the intake of dietary fibre, vegetables , fruits, processed meat, frequency of eating per day, intake of commercial foods per week and leisure time physical activity by the subjects in both the groups .

References:
1. Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, Ringel A, Davis JM. 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;346:e8707.
2. Brown JE. What is a healthful diet. In: Nutrition now. West/Wadsworth Belmont CA, USA Second edition 1999
3. Marmot M. Fruit and vegetable intake reduces risk of fatal coronary heart disease. Eur Heart J. 2011 May; 32(10):1182-3.
4. He FJ, Nowson CA, Lucas M, MacGregor GA. Increased consumption of fruit and vegetables is related to a reduced risk of coronary heart disease: meta-analysis of cohort studies. J Hum Hypertens. 2007 Sep;21(9):717-28.
5. Crowe FL, Roddam AW, Key TJ, Appleby PN, Overvad K, Jakobsen MU et al ; European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart Study Collaborators . Fruit and vegetable intake and mortality from ischaemic heart disease: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study Eur Heart J. 2011 May;32(10):1235-43.
6. Titan SMO, Bingham S, Welch A , Luben R, Oakes S, Day N , Khaw K-T Frequency of eating and concentrations of serum cholesterol in the Norfolk population of the European prospective investigation into cancer (EPIC- Norfolk):cross sectional study. BMJ, 1 December 2001, . Vol. 323; 1286-90.
7. Nettleton JA, Diez-Roux A, Jenny NS, Fitzpatrick AL, Jacobs DR Jr. Dietary patterns, food groups, and telomere length in the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Clin Nutr. 2008 Nov;88(5):1405-12.
8. Chen GC, Lv DB, Pang Z, Dong JY, Liu QF. Dietary fiber intake and stroke risk: a meta-analysis of prospective cohort studies. Eur J Clin Nutr. 2013 Jan;67(1):96-100.
9. Cherkas LF, Hunkin JL, Kato BS, Richards JB, Gardner JP, Surdulescu GL, Kimura M, Lu X, Spector TD, Aviv A. The association between physical activity in leisure time and leukocyte telomere length. Arch Intern Med. 2008 Jan 28;168(2):154-8

Dr Mahantayya V Math

Dr Rita M Khadkikar

Dr Yashoda R Kattimani

Dr Sanhita R Walawalkar

Department of Physiology, MGM Medical College, Kamothe , Navi Mumbai-410209, Maharashtra State, India

Competing interests: None declared

Dr Mahantayya Veerabhadrayya Math, Associate Professor

Dr Rita M Khadkikar, Dr Yashoda R Kattimani , Dr Sanhita R Walawalkar

MGM Medical College,, Kamothe , Navi Mumbai,410209 Maharashtra State, India

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Congratulations to Christopher Ramsden et al on producing a study which will hopefully bring some positive changes to more than cardiovascular health alone. (1)

The modern diet has overemphasised the need to consume polyunsaturated fats in the belief that they were a healthy choice, particularly in cholesterol management. They have in fact caused cyclo-oxygenase-2 (cox-2) overexpression and therefore inflammation. Is cholesterol, which is vital for good health, the real villain in cardiovascular health? A recent article published in the BMJ (2) advised the public against consuming too many eggs as they contained cholesterol. If they didn’t there would be no egg, and indeed no chicken – quite a conundrum! Generations have been persuaded by the food and drug industry that ‘functional foods’ such as margarines fortified with EFAs will give us good health, have we been duped?

The biological mechanisms (delta 5 and delta 6 desaturases) required for the uptake of essential fatty acids such as omega 3 and 6 are impaired in those with diabetes (particularly type 2 diabetes (T2DM), a population group at high risk of cardiovascular disease).

The successful absorption of EFAs also relies on adequate levels of certain vitamins and minerals. The poor absorption of EFAs is further confounded by consuming a high carbohydrate diet such as recommended to those with T2DM.

Over nutrition triggers the onset of oxidative stress in the liver due to higher availability and oxidation of fatty acids, with development of hyperinsulinemia and insulin resistance, and omega 3 long-chain polyunsaturated FA depletion, with enhancement in the omegas 6/3 LCPUFA ratio favouring a pro-inflammatory state. (3)

Commercial food processing destroys a significant amount of EFAs, along with their oxygenating ability.

Consumption of good quality omega 6 and 3 EFAs is a haphazard affair. Polyunsaturated oils are unstable and very quickly become rancid. Oxidized fatty acids are dangerous to our health. Lipid peroxidation and oxidative stress are important factors in this damage. (4)

Further damage is also caused by heating polyunsaturated fats in cooking (particularly frying foods).

Many omega 3 research trials did not consider the omega 3/6 essential fatty acid ratio which is vital to the eicossanoid balance. The correct omega 3/6 ratio is fundamental to holistic health for all. I believe that with simple dietary intervention diabetes complications such as retinopathy and nephropathy, could be ameliorated or prevented. Of real concern is the epidemic of T2DM in young people encompassing those of reproductive age. Healthy fertility and reproduction fundamentally rely on good nutrition, including EFAs in plentiful supply. Poor maternal health is a cause for concern and may predict poor health in the next generations.

As the study authors suggest their findings may have important implications for worldwide dietary advice. In this context it would be helpful to look at different aspects of the trial not just dietary fats. The study may reflect the benefits of the Australian lifestyle, level of exercise, vitamin and mineral status, quality of meat (including the quality and method of animal feeding/farming), quality of fats and oils, fish consumption, consumption of processed/fried foods and carbohydrate intake. The study of fats and lipids is a highly complex matter warranting a holistic approach. I hope further studies on this subject can also be aimed at primary prevention of disease with potentially promising results.

(1) Christopher E Ramsden, Daisy Zamora, Boonseng Leelarthaepin, Sharon F Majchrzak-Hong, Keturah R Faurot, Chirayath M Suchindran, Amit Ringel, John M Davis, Joseph R Hibbeln, Use o f 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;346:e8707

(2) Ying Rong, Li Chen, Tingting Zhu, Yadong Song, Miao Yu, Zhilei Shan, Amanda Sands, Frank B Hu, Liegang Liu, Egg consumption and risk of coronary heart disease and stroke: dose-response meta-analysis of prospective cohort studies. BMJ 2013;346:e8539

(3) Valenzuela R, Videla LA.The importance of the long-chain polyunsaturated fatty acid n-6/n-3 ratio in development of non-alcoholic fatty liver associated with obesity. Food Funct. 2011 Nov;2(11):644-8. doi: 10.1039/c1fo10133a. Epub 2011 Oct 19.
(4) Moore, K., and L. J. Roberts 2nd. 1998. Measurement of lipid peroxidation. Free Radic. Res. 28: 659–671

Competing interests: None declared

Jane E Collis, Independent Researcher

No affiliation, Kenilworth Warks UK

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A diverse range of responses can be seen at the Australian Science Media Centre site, from a range of experts highlighting some of the limitations and strengths of the study especially in relation to trans-fats and limitations of statistical analysis.
http://www.smc.org.au/2013/02/round-up-dietary-fats-and-heart-disease-bm...

Competing interests: Professional Associations for which I am a member eg Dietitians Association of Australia have a number of corporate sponsors, although I have no direct links

David M Driscoll, Exercise Physiologist and Dietitian

private practice, East Sydney 2010 Australia

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Poly unsaturated fatty acids (PUFA) are essential fatty acids to be supplied in the diet. These are important for membrane function, producing eicosanoids; the endocannabinoids, the lipoxins and resolvins form lipid rafts for cellular signaling, act on DNA, activating or inhibiting transcription factors such as NF-κB - playing a vital role in physiological functions of the body. Yet there needs to be a balance between its intake and the form of PUFA taken in the diet.

Being polyunsaturated, they generate free radicals, cause lipid peroxidation and damage mitochondrial function. It is suggested that the intake of PUFA must be accompanied by adequate amounts of intake of anti-oxidants such as vitamin E. Human body and its metabolism cannot be viewed as parts but as whole body metabolism. Whole body metabolism needs to be viewed with the interplay of internal and external factors that regulate and maintain homeostasis. Extracellular factors including the dietary constituents need to be balanced with the internal physiological mileu unique to every individual. We need to remember the Daedalus effect: for every remedy there is an adverse side effect. How we balance them is the duty of true science that will help promote health.

Competing interests: None declared

dhastagir s sheriff, Professor

Faculty of Medicine, Benghazi University, Benghazi, Libya

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To the Editors,

The study entitled “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” has a serious flaw. The PUFA-supplemented (intervention) group may have been provided with atherogenic trans fat, and the investigators cannot prove otherwise. In this report Ramsden et al. used updated statistical techniques and new clinical end points endpoints to reanalyze data from a study conducted from 1966-1973 where young and mid-aged male participants with a history of CVD were instructed to reduce dietary saturated fat and replace calories with about 15% of dietary energy coming from PUFA (1,2). Participants in the intervention group were offered both safflower-based margarine and safflower oil because the investigators presumed these two fat sources are nutritional equivalents. They were probably not the same.

Participants in the intervention group consumed “Miracle” Margarine, a product based on safflower oil. Hydrogenation of safflower oil itself creates a grainy product low in linoleic acid, so high-linoleic safflower oil margarine products were created by blending liquid safflower oil with another hydrogenated oil stock (3). Miracle Margarine used in the original study was either low in linoleic acid (due to hydrogenation of the safflower oil itself) or the oil was blended with another commercially hydrogenated fat to create a plastic margarine product. An investigation by Bernfeld, Homburger, & Kelley, published in 1962, indicated that the fatty acid composition of most margarines of the time were about 50-60% 18:1 monounsaturated fats (including oleic and trans isomers) and about 20-30% 18:2 linoleic acid, even in those products having high-PUFA claims on the label (4). None of the 22 margarines studied had a majority of fatty acids coming from PUFA. Another report from the same time period indicates that commercially produced hydrogenated fats, like those added to safflower oil to make margarine, were generally composed of about 25-40% trans fats (5). Fatty acid composition of margarines in the 1960s investigation were not comparable to liquid vegetable oil, despite package claims. The only reference supporting the healthful content of Miracle Margarine is a very general press release from the company who made the product (6). It is probable that Miracle Margarine had significant trans fatty acid content. An independent chemical analysis would have confirmed whether the composition of Miracle Margarine differed from other commercially available margarines or safflower oil. Though trans fats were not yet conclusively implicated in CVD risk at the time of the original study, scientists in the mid 20th century suspected hydrogenated fats were not healthful (5).

The authors noted that the lack of trans fat quantification was a limitation of the study (1). Ramsden et al., used an analysis of MUFA as a surrogate for trans fats, but MUFA cannot stand-in for trans fats because there are too many healthful sources of dietary MUFA. Atherogenic trans fats may have been provided to the participants as a part of the intervention, and such an addition of trans fats could have been responsible for an increase in all-cause mortality. As an editorial piece related to this study points out, interpretation of dietary studies where multiple fatty acid components are changed must be interpreted with caution (7). In the case of this reanalysis, readers should exercise caution in attributing the results to dietary PUFA when the intervention group received PUFA sources that were likely laced with trans fats.

In addition to increasing PUFA intake, participants in the intervention group reported reduced dietary saturated fat, cholesterol, and calorie intake from baseline. A negative energy balance was verified with a slight mean drop in BMI. As expected, circulating total cholesterol and triglycerides were reduced in the intervention group, but mortality outcomes were not improved consequent to these circulating lipid and anthropometric changes, which is unexpected and interesting. The more important question arising from this study may be why a dietary intervention that improved all of these commonly used surrogate end points did not reduce all-cause mortality?

Sincerely,
Jean Gutierrez, PhD, RD
Assistant Professor of Exercise Science
The George Washington University

References
1. Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, Ringel A, Davis JM. 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;346:e8707.
2. Woodhill JM, Palmer AJ, Leelarthaepin B, McGilchrist C, Blacket RB. Low fat, low cholesterol diet in secondary prevention of coronary heart disease. Adv Exp Med Biol1978;109:317-30.
3. Blum JE. The role of safflower oil in edible oil applications. J Am Oil Chem Soc. 1966 Jun;43(6):416-7.
4. Bernfeld P, Homburger F, Kelley TF. Fatty acid contents of margarines and other table fats. Am J Clin Nutr. 1962 Dec;11:554-8.
5. Brown JB. Changes in nutritive value of food fats during processing and cooking. Nutr Rev. 1959 Nov;17:321-5.
6. Significant points from the annual report of Marrickville Holdings. Sydney Morning Herald1965 Nov 19.
7. Calder P. Old study sheds new light on the fatty acids and cardiovascular health debate. BMJ. 2013:346:f493.

Competing interests: None declared

Jean L Gutierrez, University Faculty/Assistant Professor

The George Washington University, 2033 K St. NW, Suite 210V, Washington, DC20006

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what a marvellous job by the authors on a potentially paradigm-shifting endeavour akin to throwing a pebble into a pond and hanging around anxiously to see what the ripples will be.

in a nutshell, the study shows LA is a 'substrate' for oxidative stress convertible to toxic derivatives, mechanistically adverse to the cardiovascular-coronary integrity;

an otherwise good dietary item, LA's bad company (smoke/alcohol) wrecks its good potential.

the methodological and statistical avenues in use here are impeccable;

what remains is to see how the study as done can be reproduced in the larger context;

as well as some better pruning in the non-intervention group to minimise dietary components veering in the direction of the control without at the same time undermining the non-intervention integrity of the cohort.

it will also be nice to see whether n-3 fatty acids or other non n-6 species can be just as vulnerable substrates to oxidative stress or other free radical mediated insults.

the impact implicit to this study is potentially major and multivalent (clinical, nutritional, industrial pharmaceutical etc) and so reproducibility studies/checks need be carried out sooner rather than later to leave no ripples in the pond for too long .

until such cross-checking is done and unambiguously similar evidence based results emerge, it may be premature to demand that our pts start cutting new teeth inside their lipid cuisines;

but never wrong to insist on continuing avoidance of what remains a consensus; smoking and alcohol with all of their evidently deleterious effects, alone or in combination.

Competing interests: None declared

basil b FADIPE, surgeon

justin fadipe centre, mero heights. commonwealth of dominca

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