Omega-3s and AF: No Added Risk From Eating Fish but High-Dose Supplement Questions Persist

Megan Brooks

July 19, 2023

Regular consumption of fish and other foods rich in omega-3 fatty acids (FA) won't raise an individual's risk for developing atrial fibrillation (AF), suggests a meta-analysis of population-based studies.

The finding may alleviate recent concerns about higher-dose omega-3 FA supplement intake in clinical-trial patients at elevated cardiovascular (CV) risk, researchers say.

Indeed, across the 17 cohort studies in the meta-analysis, risk for incident AF was unaffected by elevated circulating and adipose tissue levels of eicosapentaenoic acid (EPA) from dietary intake. Moreover, the risk appeared to drop significantly with such levels of docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and EPA plus DHA.

The signals of AF risk associated with high-dose omega-3 FA in supplements or prescription form in some clinical trials "may not necessarily be generalizable to lower-dose habitual dietary omega-3 intakes," concludes the study's report published July 17 in the Journal of the American College of Cardiology.

Other recent research suggests that any elevated AF risk from omega-3 FA intake is dose-related and may be associated with omega-3 FA supplement or medication intake in high doses, such as 4 g/day.

"Coupled with the more consistent benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption should be maintained," conclude the authors of the report, led by Frank Qian, MD, MPH, Harvard T.H. Chan School of Public Health and Beth Israel Deaconess Medical Center, Boston, Massachusetts.

The current study is "important in showing that physiologic levels of omega-3s that would accumulate through diet don't seem to increase the risk of arrhythmia," preventive cardiologist Sean Heffron, MD, NYU Langone Health and Grossman School of Medicine, New York City, told | Medscape Cardiology.

"It also lends credence to the fact that the increased risk is specific to the high dose supplementation, because that's the only instance in which we've seen increased atrial fibrillation in association with omega-3s," said Heffron, who wasn't involved in the meta-analysis.

An accompanying editorial agrees. "Based on present evidence, moderate dietary intake of fish and seafood is unlikely to achieve sufficiently high levels of omega-3-FAs in blood or tissue that would result in increased AF risk as observed in clinical trials of fish oil supplements and high-dose prescriptions," write Christie Ballantyne, MD, and Xiaoming Jia, MD, Baylor College of Medicine, Houston, Texas.

Therefore, they conclude, "fish should continue to be an important part of the menu of a heart-healthy diet."

The meta-analysis comprised 54,799 participants from 21 countries worldwide in 17 prospective cohort studies that yielded data on incident AF, in whom there were 7720 cases of the arrhythmia over a median follow-up of 13 years. It looked at associations between such cases and levels of omega-3 FA in blood and adipose tissue samples.

In multivariable analysis, EPA levels were not associated with incident AF, with a hazard ratio (HR) of 1.00 (95% CI, 0.95 - 1.05) per interquintile range, which the report describes as the difference between the 90th and 10th percentiles.

In contrast, levels of DPA, DHA, and EPA plus DHA were all associated with reduced AF incidence at interquintile-range HRs of:

  • 0.89 (95% CI, 0.83 - 0.95) for DPA;

  • 0.90 (95% CI, 0.85 - 0.96) for DHA; and

  • 0.93 (95% CI, 0.87 - 0.99) for EPA and DHA combined.

"We found little evidence that the associations significantly varied by age, sex, or global region, or across the various lipid compartments," the report states. "Moreover, the relationship between omega-3 fatty acids and AF did not significantly differ among individuals at higher CV risk."

The authors observe that the prevalence of omega-3 FA supplement use in the cohorts was very low, suggesting that the omega-3 FA biomarker levels largely reflected habitual dietary intake.

Most of the meta-analysis population were free of CV disease or at relatively low CV risk, they write, and "it is conceivable that the effects of omega-3 fatty acids on atrial arrhythmias may differ in those with existing CV disease vs without."

However, they note, in a prespecified subgroup analysis of participants mirroring the REDUCE-IT cohort of people with established CV disease or at elevated CV risk, no association with incident AF was observed for EPA and inverse associations emerged for DPA, DHA, and EPA plus DHA.

In their editorial, Ballantyne and Jia say the meta-analysis "represents the largest epidemiological study assessing laboratory-measured omega-3 fatty acid concentrations and AF risk in the general population."

But significant heterogeneity across the studies and their populations is a major limitation of the analysis, they write, and made for differences in protocols, sample preparation, outcomes ascertainment, follow-up time, and other variables.

"Despite a rigorous approach to harmonize the data across cohorts and adjusting for multiple confounders," note Ballantyne and Jia, "observational studies always have potential for residual confounders."

The findings support fish consumption as heart-healthy, they write, but "clinicians should be aware of and discuss with patients the risks vs benefits when prescribing high-dose omega-3 FA therapies."

The Fatty Acid Research Institute retrospectively provided a small honorarium to a subset of the analysts who participated in this study, but it had no role in its design, analysis, manuscript writing, or decision to submit for publication, the report states. Disclosures for the study authors are in the report. Ballantyne received grant/research support through his institution from Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, Novartis, and Regeneron; and consulting fees from Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Esperion, Genentech, Gilead, Matinas BioPharma, Merck, New Amsterdam, Novartis, Pfizer, and Regeneron. Heffron and Jia have disclosed no relevant financial relationships.

J Am Coll Cardiol. 2023;82(4):336-349, 350-352. Abstract, Editorial

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