11th October 2023, Dr Chee L Khoo
Current U.S. dietary guidelines do recommend higher intake of omega-6 polyunsaturated fatty acids (n-6 PUFA) to reduce the risk of coronary heart disease (1,2). This pro-Omega-6 fatty acid stance remains rather contentious. While there is data supporting cholesterol benefits of linoleic acid (LA), the predominant dietary n-6 PUFA and higher dietary n-6 PUFA (predominantly LA) is associated with lower CHD risk in prospective cohort studies (3), not all cohort studies have confirmed these benefits (4). Older, randomised trials utilising LA-rich vegetable oils did not consistently reduce risk of CHD (4,5). While a 2018 review found that an increased intake of n-6 PUFA has been shown to reduce cholesterol and may reduce myocardial infarction it did not lower LDL cholesterol and triglycerides [6]. Further, a subsequent 2021 review found that O6PUFA do not affect the risk of CVD morbidity and mortality.[7]. Very confusing.
Omega-3 polyunsaturated fatty acids (n-3 PUFA) and n-6 PUFA are polyunsaturated fatty acids characterised by the presence of a double bond, either three or six atoms away from the terminal methyl group in their chemical structure. The three types common O3PUFA involved in human physiology are α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). There are many different omega-6 fatty acids (γ-linolenic acid (GLA), dihomo-γ-linoleinc acid (DGLA), and ARA), but the main one is linolenic acid (LA). In the human body, these fatty acids (FAs) give rise to arachidonic acid (ARA), eicosapentaenoic acid and docosahexaenoic acid that play key roles in regulating body homeostasis. In general, ARA gives rise to pro-inflammatory eicosanoids whereas EPA and DHA give rise to anti-inflammatory eicosanoids.
ALA can be found in plants, while DHA and EPA are found in algae and fish. Common sources of plant oils containing ALA include walnuts, edible seeds, and flaxseeds as well as hempseed oil. In contrast, while LA can be found in poultry, eggs, nuts and seeds, vegetable oils is the major source of omega-6 fatty acids.
There may be many reasons why the data is conflicting. Most of the studies utlilising LA were done on subjects who has established CVD. Studies looking at primary prevention in the general population are limited. Further, studies looking at PUFA are primarily based on subject recall and therefor subjected to recall bias. Besides, there are more than one O6PUFA. Perhaps, not all O6PUFA are the same. A recent study tried to address some of these issues.
Jason Wu et al. prospectively designed and assessed the association of circulating n-6 PUFA biomarkers with total and cause-specific mortality in the Cardiovascular Health Study (CHS), a community-based cohort of older U.S. adults. Circulating LA are objective biomarkers of LA intake (rather than relying on patient recall). They also looked at the other members of the O6PUFA as well looked at the contribution of O3PUFA to the mortality rate.
Plasma phospholipid fatty acids were measured in 2792 study participants without cardiovascular disease (CVD) from available blood samples collected and stored from the Cardiovascular Health Study (CHS). The CHS was a multicentre, community-based, prospective cohort of non-institutional adults >65 years old recruited from 1992 to 1993. The blood samples were considered as baseline levels. Subjects were followed up annually. The association between LA and CV and all-cause mortality is based on plasma phospholipid levels which avoids the inaccuracy of dietary recalls.
During 34 291 years of follow-up, 1994 deaths occurred (incidence rate, 5.8 per 100 person-years). After adjustment for demographic, lifestyle, cardiovascular and dietary risk factors, circulating LA was inversely associated with a 13% lower risk in total mortality (p for trend=0.005) among participants in the highest compared to the lowest quintile. For each 1 SD higher LA was associated with 7% lower total mortality.
When they adjusted for potential confounders or intermediate risk factors including low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, and fibrinogen, the inverse associations of LA with total mortality slightly attenuated. Further adjustment for use of lipid medication, aspirin use, and consumption of fruits, vegetables, dietary fibre, and red meat did not materially alter the results.
LA was associated with 22% lower CVD mortality in the top versus bottom p for trend=0.02). In particular, LA most strongly associated with 49% lower risk of non-arrhythmic CHD mortality and heart failure across quintiles (p for trend=0.001) but not with arrhythmic CHD mortality.
The other n-6 PUFA (GLA, DGLA, or AA) were not associated with higher or lower total or CVD mortality.
Humans lack the enzyme required for the insertion of a cis double bond at 3rd and 6th carbon of n-3 and n-6 PUFA respectively, thus making these fatty acids essential. Alpha-linolenic acid (ALA) and linoleic acid (LA) must therefore be obtained from the diet. From LA, arachidonic acid (ARA) is synthesised. ARA is the precursor in the biosynthesis of our prostaglandins, thromboxanes and leukotrienes which are inflammatory mediators. On the other hand, ALA goes on to become EPA and DHA which are essential for many vital organ function as well as to counter the inflammatory mediators. Both pathways share the same enzymes and there is a worry that too much of O6PUFA may compete for the same enzymes for the formation of EPA and DHA.
This study provides no evidence for interaction between n-6 PUFA and n-3 PUFA for risk of mortality in older adults, and indeed support independent benefits of each for total and CVD mortality, with lowest mortality risk among people having highest biomarker levels of each. In fact, those with the highest circulating levels of both LA and n-3 PUFA had 54% lower risk of total mortality compared with those with lowest levels of both.
Two previous studies from Finland and Sweden found similar inverse association between LA and total mortality in middle-aged men (8,9).
Another very interesting finding from the study is the relation between dietary n-6 PUFA and plasma phospholipid levels. Plasma LA showed the greatest dose–response association with intake of LA up to ≈8% of total daily energy, with relatively smaller increases at intakes>8%. Perhaps, LA is beneficial up to a certain level of total daily energy intake.
Now the study by Jason Wu et al is now 10 years old. Nothing much have come out that has gone against those findings. In fact, a recent update by Djuricic and Calder (2021) concluded that “Although the eicosanoid mediators produced from the omega-6 PUFA AA are mainly pro-inflammatory in character, current evidence shows only limited effect of LA and AA on inflammatory biomarkers at intakes currently consumed in human diets. Furthermore, AA, similar to DHA, is important in brain development and cognitive function.” (10).
In summary, not all n-6 PUFA are the same. In the study by Jason Wu et al, it appears that LA is beneficial in lower overall mortality as well as cardiovascular mortality. LA is not a totally bad guy after all. But then, this is one of many studies about n-6 PUFA.
References:
- US Department of Agriculture, US Department of Health and Human Services. Dietary Guidelines for Americans. 7th ed. Washington DC: UC Government Printing Office, 2010.
- Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL, Appel LJ, Engler MM, Engler MB, Sacks F. Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation. 2009;119:902–907.
- 4. Jakobsen MU, O’Reilly EJ, Heitmann BL, Pereira MA, Bälter K, Fraser GE, Goldbourt U, Hallmans G, Knekt P, Liu S, Pietinen P, Spiegelman D, Stevens J, Virtamo J, Willett WC, Ascherio A. Major types of dietary fat and risk of coronary heart disease: a pooled analysis of 11 cohort studies. Am J Clin Nutr. 2009;89:1425–1432.
- 5. Chowdhury R, Warnakula S, Kunutsor S, Crowe F, Ward HA, Johnson L, Franco OH, Butterworth AS, Forouhi NG, Thompson SG, Khaw KT, Mozaffarian D, Danesh J, Di Angelantonio E. Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis. Ann Intern Med. 2014;160:398–406.
- 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;346:e8707.
- Hooper L, Al-Khudairy L, Abdelhamid AS, Rees K, Brainard JS, Brown TJ, Ajabnoor SM, O’Brien AT, Winstanley LE, Donaldson DH, Song F, Deane KH (2018). “Omega‐6 fats for the primary and secondary prevention of cardiovascular disease”. Cochrane Database of Systematic Reviews. 11. CD011094
- Hooper L, Al-Khudairy L, Abdelhamid AS, Rees K, Brainard JS, Brown TJ, Ajabnoor SM, O’Brien AT, Winstanley LE, Donaldson DH, Song F, Deane KH (2018). “Omega‐6 fats for the primary and secondary prevention of cardiovascular disease”. Cochrane Database of Systematic Reviews. 11. CD011094
- Laaksonen DE, Nyyssönen K, Niskanen L, Rissanen TH, Salonen JT. Prediction of cardiovascular mortality in middle-aged men by dietary and serum linoleic and polyunsaturated fatty acids. Arch Intern Med. 2005;165:193–199.
- Warensjö E, Sundström J, Vessby B, Cederholm T, Risérus U. Markers of dietary fat quality and fatty acid desaturation as predictors of total and cardiovascular mortality: a population-based prospective study. Am J Clin Nutr. 2008;88:203–209.
- Djuricic I, Calder PC. Beneficial Outcomes of Omega-6 and Omega-3 Polyunsaturated Fatty Acids on Human Health: An Update for 2021. Nutrients. 2021 Jul 15;13(7):2421. doi: 10.3390/nu13072421.