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The journal Current Atherosclerosis Reports has published a synthesis of the latest evidence of the role of omega-3 fatty acids in cardiovascular health, specifically research published between 2020 to 2025 regarding EPA and DHA. This review includes a discussion of biological mechanisms as well as a review of clinical evidence, including both observational and randomized and controlled trials, and an update on the association with atrial fibrillation.
The primary mechanisms of action outlined in this paper include improved lipid metabolism, anti-inflammatory, anti-arrhythmic, and anti-thrombotic effects, as well as enhanced endothelial function. For example, EPA and DHA enhance fatty acid oxidation, reduce synthesis of very-low-density lipoproteins (VLDLs), and lower triglyceride levels, in part mediated by activation of the peroxisome proliferator-activated receptor (PPAR) α. In animal studies, these effects on energy metabolism have been linked to slower organ aging. Distinctions between EPA and DHA are also discussed; for one, DHA but not EPA can modestly raise LDL-C levels but not ApoB, which points to a less atherogenic shift, while EPA is more likely to inhibit the oxidation of small dense LDL.
One of the anti-inflammatory mechanisms reviewed is recent data indicating that EPA/DHA modulates the gut microbiome. This includes increasing the abundance of beneficial organisms such as Bifidobacterium and Lactobacillus, while decreasing the pathogenicity of others (Enterobacteriaceae). EPA and DHA may also modulate the ratio of Firmicutes to Bacteroidetes, itself associated with the risk for obesity, NAFLD, etc., as well as the production of anti-inflammatory short-chain fatty acids, such as butyrate.
A recent area of concern has been the association between omega-3 fatty acids and arrhythmias, specifically atrial fibrillation. Omega-3s are generally thought to have antiarrhythmic effects through multiple mechanisms, including improvement of cardiac cell function and membrane fluidity, and modulation of sodium, potassium, and calcium currents. In 2023, the Journal of the American College of Cardiology published an analysis of 17 prospective cohort studies with nearly 55,000 participants, evaluating the relationship between blood or tissue omega-3 levels and incident atrial fibrillation. After multivariate analysis, EPA was not associated with atrial fibrillation, but DPA, DHA, and EPA+DHA were all associated with a small decrease in the incidence of atrial fibrillation. Similarly, the Million Veteran program, which included data on the omega-3 intake of over 300,000 veterans, found a reduction in atrial fibrillation with increasing intake, with a plateau at approximately 750 mg per day.
However, it has been suggested that high-dose omega-3s may modulate PIEZO1 channel activity (influencing calcium influx), and potentially increase the risk for atrial fibrillation. For example, a prospective cohort study published in BMJ Medicine found a small increase in the risk for atrial fibrillation among healthy adults when taking fish oil supplements. It’s important to note that this study was not a controlled trial (no dosage or formulation information was available), and does not show causality.
The form of omega-3s does appear to be important. One of the first studies to suggest a link between omega-3s and atrial fibrillation was published in NEJM, and found that although the prescription-only form, Icosapent ethyl (IPE), was associated with a reduction in cardiovascular events and death, it was also associated with a small increase in atrial fibrillation risk (3.1% vs. 2.1% with placebo). The RESPECT-EPA randomized trial also reported an increase in atrial fibrillation risk as a secondary outcome when using IPE vs. control.
IPE has been compared to DHA/EPA (as ethyl esters), but not in a controlled trial. In one retrospective cohort study published in the Journal of the American Heart Association, over 17,000 participants were taking either Icosapent ethyl (IPE) or DHA/EPA in conjunction with a statin for dyslipidemia. In this study, IPE was associated with a greater risk for atrial fibrillation than DHA/EPA (5.2% vs. 4.07%). The other prescription form of omega-3, a carboxylic acid formulation, was also shown to increase the risk for atrial fibrillation compared to placebo in a large clinical trial, but only as a tertiary outcome.
Indeed, the association has largely been found as a secondary or exploratory outcome of clinical trials, not the primary outcome. One exception to this is a randomized controlled trial published in JAMA, which evaluated vitamin D supplementation, EPA/DHA supplementation, or the combination of the above, each compared to placebo, with atrial fibrillation as the primary outcome in a study that included over 25,000 participants. Over a median of 5 years of follow-up, no significant difference in atrial fibrillation was observed for any of the above groups compared to placebo. Thus, the risk of atrial fibrillation with omega-3s seems to be largely associated with prescription forms of omega-3s or at very high doses, and even then, only as secondary or tertiary outcomes.
Lastly, it’s important to note that the recently published synthesis generally points to favorable effects on cardiovascular health with EPA/DHA supplementation, even among people with atrial fibrillation. For instance, a meta-analysis of 13 randomized and controlled trials published in the Journal of the American Heart Association found lower risk for myocardial infarction, coronary heart disease (CHD) death, total CHD, cardiovascular disease (CVD) death, and total CVD, with risk reductions linearly related to dose. Additionally, a 2024 meta-analysis evaluating the bleeding risk from omega-3s, also published in the Journal of the American Heart Association, found no significant increase in risk for bleeding, with the exception of the prescription IPE form.
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