Inverse linear relationship between dietary linoleic content and coronary heart disease risk

Dietary Linoleic Acid and Risk of Coronary Heart Disease: A Systematic Review and Meta-Analysis of Prospective Cohort Studies

Literature - Farvid MS et al., Circulation. 2014

Farvid MS, Ding M, Pan A et al.
Circulation. Oct 28. 2014;130:1568-1578


Higher consumption of poly-unsaturated fatty acids (PUFAs) as opposed to trans-fat and saturated fatty acids (SFA) is recommended to reduce the risk of coronary heart disease (CHD) [1,2]. Most attention has been given to the effect on CHD risk of n-3 PUFA (including long chain n-3 and α-linoleic acid (ALA)).
Linoleic acid (LA) is the predominant n-6 PUFA in the Western diet, as a component of vegetable oils and nuts. Evidence suggests that higher LA reduces risk factors for CHD, as it was found to lower LDL-c [3-6], to improve insulin sensitivity [3,7], and to lower risk of hypertension [8,9]. Thus also substituting SFAs with n-6 PUFAs has been recommended, although concerns have been raised about high LA consumption due to its potential pro-inflammatory and thrombogenic properties [10-13]. Randomised controlled feeding studies did not support this hypothesis.
Several studies have looked at the relation between n-6 PUFA or LA with risk of CHD, but led to inconclusive results. A systematic review and meta-analysis of prospective cohort studies was therefore conducted to investigate the association between dietary LA intake and CHD endpoint in generally healthy populations. Mean LA consumption varied substantially across studies (median intakes ranging from 1.5% to 6.4% of energy, 10th-90th percent range from 1.1% to 9.5%).

Main results

  • Considering 14 estimates of the association between LA and total CHD events (from 10 cohort studies), LA consumption was inversely associated with risk of total CHD events. The fixed-effect summary of RR for the highest compared to the lowest intake category was 0.85 (95%CI: 0.78-0.92, medium heterogeneity (I2=35.5%). A random-effects model gave very similar results.
  • No significant sources of heterogeneity were identified in a meta-regression analysis.
  • Higher LA intake was also associated with lower risk of CHD mortality (fixed effect summary of RR for highest compared to lowest category: 0.79, 95%CI: 0.71-0.89).
  • A dose-response analysis revealed a linear association between LA intake and CHD events and CHD death. 5% higher energy intake from LA was associated with a 10% lower risk of CHD events (RR: 0.90, 95%CI: 0.85-0.94, I2=44.6%) and 13% lower risk of CHD death (RR: 0.87, 95%CI: 0.81-0.93).
  • 9 cohort studies evaluated substitution of LA for carbohydrate showed that substituting 5% energy intake from LA for carbohydrates lowered risk with about 10%. A slightly lower risk benefit was seen for substitution of LA for SFA.

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This systematic review and meta-analysis suggest a that risk of CHD decreases with higher dietary LA intake, when replacing either carbohydrate or saturated fat. Inverse linear dose-response relationships were seen between dietary LA intake and both total CHD events and CHD deaths. These data support current recommendations to replace saturated fat with LA for primary prevention of CHD in the general population, as previously postulated harmful effects of high LA consumption were not confirmed in these analyses.

Editorial comment [14]

“The LA-is-harmful hypothesis depends heavily on the view that an LA metabolite, AA, is converted to potent proinflammatory signalling molecules. But AA is not the only LA metabolite with potential effects on CHD; LA itself can be converted to a wide variety of bioactive molecules. (…) If one examines the entire AA metabolome, one finds a constellation of metabolites, including a variety of prostaglandins, leukotrienes, ligands for endocannabinoid receptors, lipoxins, isoprostanes, nitrated AA, and epoxides, among others. Some are proinflammatory but some are anti-inflammatory or promote the resolution of inflammatory insults. Often these effects have only been observed in certain cell/tissue types and under potentially nonphysiological conditions, and their effects in normal physiology or those of other metabolites remain to be discovered. The net impact on human metabolism (and CHD risk) of this multitude of products will ultimately be determined by their interaction among themselves (and with their omega-3 fatty acid analogues) and is virtually impossible to predict.
(…) Suffice it to say that large-scale, multiyear intervention trials in which one major dietary component is (must be) substituted for another are both difficult to conduct and to interpret because of the multiple variables involved.(…) Importantly, the current data continue to support the recommendation of many health authorities for 5% to 10% of energy as LA.”

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