Are Omega-3 Fatty Acids Pro-arrhythmic or Anti-arrhythmic?

Came across a review article titled “Omega-3 Fatty Acids and Arrhythmias” in Circulation [1], which was quite interesting to read. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the primary omega-3 polyunsaturated fatty acids (n-3 PUFAs) which have been studied extensively. They have beneficial effects in ischemic heart disease. But their role in cardiac arrhythmias is not that well established.

REDUCE-IT [2] was a landmark trial which evaluated patients with elevated triglyceride levels despite the use of statins. The trial showed that risk of ischemic events, including cardiovascular death, was significantly lower among those who received icosapent ethyl compared to placebo. Icosapent ethyl (IPE) is a highly purified synthetic EPA. But a larger percentage of patients in the icosapent ethyl group compared to placebo were hospitalized with atrial fibrillation or flutter (3.1% vs. 2.1%, P=0.004), raising concerns of a proarrhythmic effect for IPE.

A systematic review and meta-analysis [3] evaluated the role of long-term marine omega-3 fatty acids supplementation on the risk of atrial fibrillation in randomized controlled trials. They concluded that marine omega-3 fatty acids supplementation was associated with an increased risk of atrial fibrillation. The risk appeared to be greater in trials testing more than one gram per day.

Initial animal studies suggested the n-3 PUFAs have a role in prevention of sudden cardiac death after acute myocardial infarction. In that context, mechanism of arrhythmic death is polymorphic ventricular tachycardia and ventricular fibrillation. This is unlike the scar related monomorphic ventricular tachycardia which occurs at a later stage. But clinical trials invoking this concept led to a null result, though initial epidemiological data had shown a beneficial effect in reducing sudden cardiac death with n-3 PUFA [1]. Reason for the null results in contemporary trials may be because of advancement in invasive and non-invasive management compared the era prior to that.

References

1. Marcus MD, Link MS. Omega-3 Fatty Acids and Arrhythmias. Circulation. 2024 Aug 6;150(6):488-503. doi: 10.1161/CIRCULATIONAHA.123.065769. Epub 2024 Aug 5. PMID: 39102482.
2. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22. doi: 10.1056/NEJMoa1812792. Epub 2018 Nov 10. PMID: 30415628.
3. Gencer B, Djousse L, Al-Ramady OT, Cook NR, Manson JE, Albert CM. Effect of Long-Term Marine ɷ-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. Circulation. 2021 Dec 21;144(25):1981-1990. doi: 10.1161/CIRCULATIONAHA.121.055654. Epub 2021 Oct 6. PMID: 34612056; PMCID: PMC9109217.