Fish oil supplements beat oily fish at reducing harmful blood vesicles

A high-dose fish oil supplement slashed clot-promoting blood vesicles in healthy adults—outperforming oily fish and pointing to EPA as the key driver behind these cardiovascular benefits.

Accepted manuscript: High dose fish oil supplements are more effective than oily fish in altering the number and function of extracellular vesicles in healthy human subjects: A randomized, double-blind, placebo-controlled, parallel trial. Image Credit: Oksana Mizina / Shutterstock

In a recent study published in the British Journal of Nutrition, researchers investigated the effects of oily fish and fish oil supplements on the composition, numbers, and procoagulant activity of extracellular vesicles (EVs). EVs are naturally present in the body fluids of healthy individuals and are derived from nearly all cells under pathological and physiological conditions. EVs regulate normal physiological processes and may serve as biomarkers for cancer, cardiovascular disease (CVD), and type 2 diabetes.

Dietary n-3 polyunsaturated fatty acids (PUFAs), abundant in fish oils and oily fish, are associated with protection from CVDs. n-3 PUFA supplements reduce the risk of all-cause and CVD mortality. While there are several potential mechanisms of n-3 PUFAs' cardiovascular benefits, only a few studies explored the effect of n-3 PUFAs on EVs.

Previously, the authors reported that n-3 PUFA supplementation reduced the numbers of total EVs and EV subtypes from endothelial cells and platelets in people with moderate CVD risk. Nevertheless, data on whether oily fish intake affects EV function/numbers are lacking.

About the study

In the present study, researchers examined the effects of fish oil supplements and oily fish on EV composition, numbers, and procoagulant activity. Participants were recruited through the media. Individuals with infection, smoking, immune disorders, autoimmune disorders, neurological diseases, allergy, hypersensitivity, pregnancy, alcohol misuse, use of medications or supplements, and intolerance to fish, n-3 fats, or fish oils were excluded.

This double-blind, parallel, randomized, placebo-controlled trial allocated participants to one of three groups: fish oil supplements plus two white fish meals per week, control supplements (olive oil) plus two oily fish meals, and control supplements plus two white fish meals. Venous blood samples were obtained and processed to platelet-free plasma (PFP).

Size exclusion chromatography was used to isolate EVs, and nanoparticle tracking analysis was used to determine their size and concentration. Flow cytometry was also performed to evaluate the concentrations of EV subpopulations, such as platelet-derived EVs (PDEVs), endothelial-derived EVs (EDEVs), and phosphatidylserine (PS)-positive EVs. Lipid extracts were prepared from EVs and red blood cells (RBCs) to estimate fatty acid compositions. Thrombin generation was evaluated using a kit.

The effects of the intervention on thrombin formation were assessed in PFP samples compared to pooled vesicle-depleted plasma (VDP) alone and in VDP plus EVs compared to PFP alone. Further, the fibrinolytic activity and clot-forming capacity of EVs were assessed.

Findings

42 subjects aged 55 years or older completed the intervention. The study groups were similar in terms of physical characteristics, glucose and lipid profile, and blood pressure. The team found a significant increase in the proportions of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in RBCs and EVs following the intake of oily fish meals and fish oil supplements, with a considerable increase in total n-3 PUFAs.

Despite fish oil supplements delivering 1 g/day more EPA than oily fish meals (1.5 g vs 0.4 g), both interventions increased EPA and DHA in RBCs and EVs to a similar extent.

Notably, total n-6 PUFAs declined in RBCs with oily fish intake and fish oil supplements. No changes were observed in other fatty acids in RBCs and EVs in the fish oil-supplemented or oily fish intake groups. Besides, oily fish meals and fish oil supplements had no significant effects on the blood lipid profile. However, there were trends toward lower plasma triacylglycerol levels and increased LDL-C concentrations. Fish oil supplements significantly reduced circulating EV numbers, while oily fish intake had no effect.

Further, fish oil supplements or oily fish meals did not impact the average size of the EV population or the numbers of PDEVs, EDEVs, and PS-positive EVs. This may reflect limitations of flow cytometry, which detects only EVs larger than 200 nm, potentially missing smaller vesicles that were affected by the intervention.

PFP and EVs from fish oil-supplemented subjects had significantly reduced thrombogenic capacity compared to oily fish intake and control groups, as shown by decreased peak thrombin concentration, area under the curve (AUC), and velocity index. In addition, EVs from fish oil-supplemented and oily fish intake groups did not affect clot formation or lysis.

Notably, the proportions of eicosatetraenoic acid, EPA, total n-3 PUFAs, and DHA in EVs were significantly associated with EV numbers. Besides, the proportions of DPA, EPA, stearic acid, DHA, linoleic acid, total monounsaturated fatty acids, total n-6 PUFAs, and total n-3 PUFAs in RBCs were significantly associated with EV numbers. The proportion of EPA in EVs explained 28% of the variance in EV numbers, while EPA in RBCs explained 31.5%. EPA proportion in EVs and RBCs independently predicted EV numbers and thrombin formation.

Conclusions

The study highlighted that fish oil supplements were more effective in reducing EV numbers and their procoagulant activity than oily fish. Notably, oily fish intake and fish oil supplementation increased DHA and EPA proportions in RBCs and EVs to a similar extent despite fish oil supplements containing approximately double the total amount of EPA and DHA.

Further, EPA proportion in RBCs and EVs was associated with EV numbers and thrombin formation, suggesting EPA may be the main driver of the observed effects, based on its stronger correlations with these parameters. Overall, the findings suggest that increasing EPA consumption beyond current recommendations for oily fish intake may offer more benefits, especially in terms of EV function and numbers.