Hostname: page-component-7c8c6479df-p566r Total loading time: 0 Render date: 2024-03-27T06:49:52.135Z Has data issue: false hasContentIssue false

Response to Clifton

Published online by Cambridge University Press:  17 June 2011

Christopher E. Ramsden
Affiliation:
Section on Nutritional Neurosciences, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA email chris.ramsden@nih.gov
Joseph R. Hibbeln
Affiliation:
Section on Nutritional Neurosciences, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA email chris.ramsden@nih.gov
Sharon F. Majchrzak-Hong
Affiliation:
Section on Nutritional Neurosciences, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA email chris.ramsden@nih.gov
John M. Davis
Affiliation:
Department of Psychiatry, School of Medicine, University of Illinois, Chicago, IL, USA
Rights & Permissions [Opens in a new window]

Abstract

Type
Letter to the editor
Copyright
Copyright © The Authors 2011

We thank Dr Clifton for his interest in our paper(Reference Ramsden, Hibbeln and Majchrzak1). We would like to again clarify the central finding of our analysis, that mixed n-3/n-6 PUFA interventions had significantly different CHD effects compared with interventions selectively increasing n-6 linoleic acid (LA) (P = 0·02), determined using standard methodology for performing and interpreting heterogeneity analysis(Reference Matt, Cook, Cooper and Hedges2). As discussed in our paper and in our response to Harris et al., the mixed n-3/n-6 PUFA intervention category contains two trials that increased EPA+DHA alongside LA (EPA+DHA+LA interventions), and two trials that increased α-linolenic acid (ALA) and LA without concurrent increases in EPA+DHA (ALA+LA interventions). Because no significant heterogeneity exists between the two categories of mixed n-3/n-6 PUFA interventions (Q = 0·22, df = 1; P = 0·64), we did not previously report a comparison of LA-selective PUFA interventions with ALA+LA interventions in heterogeneity analysis. However, such an analysis performed in response to this letter demonstrates that LA-selective and ALA+LA interventions have significantly different effects on CHD risk with (Q = 5·96, df = 1; P = 0·01) or without (Q = 3·95, df = 1; P = 0·047) the inclusion of the Sydney Diet Heart Study (SDHS). This finding again emphasises the necessity of making a clear distinction among PUFA species, and further demonstrates that CHD benefits of interventions increasing both n-3 and n-6 PUFA are not necessarily attributable to n-6 LA.

Although we did not make the following conclusion in our paper, Dr Clifton attributes the conclusion that ‘interventions which contain ALA as well as LA show benefit whereas those which contain LA alone do not show benefit’ to us. We would therefore like to further clarify our findings here. Pooled analysis of all four n-6 LA-specific datasets (n 9569) shows a relatively consistent, albeit non-significant, signal towards increased risk for CHD death (+28 %, risk ratio (RR) 1·28, 95 % CI 0·96, 1·71; P = 0·09), total CHD events (+23 %, RR 1·23, 95 % CI 0·94, 1·61; P = 0·13) and death from all causes (+16 %, RR 1·16, 95 % CI 0·95, 1·42; P = 0·15). Although these findings point towards possible harm rather than benefit, the pooled 95 % CI include 1·0, therefore one should not definitively conclude that n-6 LA-specific PUFA interventions provide no benefit or cause harm. This statistical uncertainty was appropriately reflected in our conclusion stating that interventions increasing n-6 LA in place of trans-fatty acids (TFA) and SFA provide ‘no indication of benefit, and there is a possibility of harm’ and our abstract stating that ‘advice to specifically increase n-6 PUFA intake [is] unlikely to provide the intended benefits, and may actually increase the risks of CHD and death’. By contrast, pooled analysis of the two mixed n-3/n-6 PUFA interventions that increased ALA+LA without also increasing EPA+DHA shows a non-significant trend towards CHD benefit (RR 0·81, 95 % CI 0·64, 1·02; P = 0·07), rather than the signal towards harm of LA-selective PUFA interventions. Importantly, however, ALA was accompanied by large amounts of n-6 LA in both trials, as well as in a recent highly publicised negative trial(Reference Kromhout, Giltay and Geleijnse3) that used a high-LA margarine (39·8 g LA/100 g) to deliver ALA (13·7 g ALA/100 g). Because the potential metabolic benefits of ALA could be masked by the presence of large amounts of n-6 LA(Reference Ghosh, Novak and Innis4, Reference Liou, King and Zibrik5), these data should not be interpreted as ruling out the possibility of CHD benefits specific to n-3 ALA. We have no randomised controlled trial (RCT) data to evaluate the CHD effects of increasing ALA without concurrent addition of much larger amounts of LA. This critical research gap could be resolved by an RCT substituting conservative amounts of flaxseed oil (not soybean oil or ALA+LA margarine) for other fats with the evaluation of CHD outcomes.

The Minnesota Coronary Survey (MCS)(Reference Frantz, Dawson and Ashman6) provided the largest number of CHD events (252) and deaths (517) of any RCT, despite the low event rate specified by Dr Clifton. Importantly, intent-to-treat analysis of the full dataset showed more CHD events in the LA-specific PUFA group, especially in women (RR 1·31, 95 % CI 0·90, 1·90); these numbers include a curious twofold increase in CHD events (RR 2·15, 95 % CI 1·19, 3·87; P = 0·01) in women on the LA-specific PUFA intervention for 1 year or less. Although the LA-specific PUFA group remaining in the study for >1 year had slightly fewer CHD events, this subgroup excludes the LA-specific participants who had already experienced a CHD event within the first year (perhaps the most vulnerable group). MCS investigators appreciated in 1968 that the duration necessary to observe CHD effects ‘could be a long time, or the effect might very well appear immediately, if all that is required is arrest of the process, or if the mechanism of the effect is in large part through the clotting phenomenon’(Reference Frantz and Ashman7). Since dietary fatty acids alter thrombosis, arrhythmogenesis and inflammatory processes, in addition to lipoprotein metabolism and oxidation, and an alternative analytical plan was not specified(Reference Frantz and Keys8), it is most appropriate to use the ‘gold standard’ intent-to-treat methodology in evaluating CHD outcomes in all randomised participants.

We agree that TFA probably played a key confounding role in these RCT, a point overlooked in previous meta-analyses but discussed at length in our paper(Reference Ramsden, Hibbeln and Majchrzak1). It is important to note, however, that the liquid vegetable oils and cholesterol-lowering (soft) polyunsaturated margarines consumed by the experimental dieters generally contain more LA, and considerably less TFA(Reference Carpenter9), than the shortenings and common (hard) margarines consumed in moderate-to-large quantities by the control groups. RCT with experimental margarines observed that they were specially formulated to be ‘soft’ or ‘polyunsaturated’(Reference Ramsden, Hibbeln and Majchrzak1, Reference Frantz and Keys8, Reference Clarke, Hedley and Marr10, 11), or that the ‘major component is unaltered vegetable oil with a small amount of hydrogenated fat added as a hardening agent’(Reference Hiscock, Dayton and Pearce12). Likewise, the ‘Miracle’ brand margarine used in the SDHS was a polyunsaturated product formulated in ‘consultation with leading hospital authorities, physicians and dietitians’(13). Hence, because the experimental diets probably contained substantially less TFA than control diets, the reported CHD benefits of mixed n-3/n-6 PUFA interventions may have been overestimated, and the potential harm of n-6 LA-specific PUFA interventions may have been underestimated, as noted in our paper(Reference Ramsden, Hibbeln and Majchrzak1).

We agree with Dr Clifton that important evidence gaps remain, and have outlined the design of an RCT to evaluate the specific effects of lowering n-6 LA on clinical CHD outcomes in our paper and in our response to Harris et al. The results of such a trial will have major public health implications and should put this debate to rest once and for all.

Acknowledgements

The study was supported by the intramural research programme of the National Institute on Alcohol Abuse and Alcoholism. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute on Alcohol Abuse and Alcoholism or National Institutes of Health. The authors declare that they have no conflicts of interest.

References

1 Ramsden, CE, Hibbeln, JR, Majchrzak, SF, et al. (2010) 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 104, 15861600.Google Scholar
2 Matt, GE & Cook, TD (1994) Threats to the validity of research syntheses. In The Handbook of Research Synthesis, pp. 503518 [Cooper, H and Hedges, L, editors]. New York: Russel Sage Foundation.Google Scholar
3 Kromhout, D, Giltay, EJ, Geleijnse, JM, et al. (2010) n-3 Fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 363, 20152026.Google Scholar
4 Ghosh, S, Novak, EM & Innis, SM (2007) Cardiac proinflammatory pathways are altered with different dietary n-6 linoleic to n-3 alpha-linolenic acid ratios in normal, fat-fed pigs. Am J Physiol Heart Circ Physiol 293, H2919H2927.Google Scholar
5 Liou, YA, King, DJ, Zibrik, D, et al. (2007) Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men. J Nutr 137, 945952.Google Scholar
6 Frantz, ID Jr, Dawson, EA, Ashman, PL, et al. (1989) Test of effect of lipid lowering by diet on cardiovascular risk. The Minnesota Coronary Survey. Arteriosclerosis 9, 129135.Google Scholar
7 Frantz, ID Jr & Ashman, PL (1968) Design of dietary experiments for preventing myocardial infarction. J Am Diet Assoc 52, 293299.Google Scholar
8 Frantz, ID Jr & Keys, A (1967) R01 HE 0986-03 Research Grant Application: Effect of a Dietary Change on Human Cardiovascular Disease “The Minnesota Coronary Survey”.Google Scholar
9 Carpenter, DL (1973) Lipid composition of selected margarines. J Am Oil Chem Soc 50, 372376.Google Scholar
10 Clarke, JAC, Hedley, E, Marr, JW, et al. (1969) Dietary aspects of a controlled trial of soya-bean oil in myocardial infarction. Int J Food Sci Nutr 23, 136150.Google Scholar
11 Executive Committee on Diet and Heart Disease (1968) National Diet-Heart Study Report. Chapter XVII: Faribault Second Study. Circulation, 37–38, I260I274.Google Scholar
12 Hiscock, E, Dayton, S, Pearce, ML, et al. (1962) A palatable diet high in unsaturated fat. J Am Diet Assoc 40, 427431.Google Scholar
13 Significant Points from the Annual Report of Marrickville Holdings (1965) Sydney Morning Herald (19 November 1965). Sydney, Australia.Google Scholar