In vivo levels of omega-3 fatty acids are not associated with increased risk of incident atrial fibrillation (AF), say researchers, who highlight their health benefits as reason to continue with current guidelines. Published in the July 25 issue of the Journal of the American College of Cardiology, data from the global, harmonized, pooled analysis suggest the safety of habitual dietary intakes of omega-3 fatty acids with respect to AF risk. The analysis also recommends that future clinical trials investigating eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) supplementation include AF as an adjudicated outcome. Confounding by diet and lifestyle “To our knowledge, our study is the largest investigation to date to examine the association between in vivo omega-3 fatty acid status and incident AF,” says the study. “Whether these associations represent a true independent effect or merely a reflection of the correlation with seafood intake and related lifestyle factors warrants further research. The difference in associations for EPA vs DHA, both of which are correlated with seafood consumption, and the significantly lower risk for DPA, which is endogenously regulated and very weakly correlated with diet, suggest that confounding by diet and lifestyle is unlikely to fully explain our observations.” Results from participant-level data from 17 prospective cohort studies revealed that among the 54,799 participants, 7,720 incident AF cases were ascertained after a median 13.3 years of follow-up. Multivariable analysis also revealed that EPA levels were not associated with incident AF with hazard ratio [HR] per interquintile range (i.e., the difference between the 90th and 10th percentiles) recorded as 1.00 (95% confidence interval [CI]: 0.95-1.05). HRs for higher levels of DPA were 0.89 (95% CI: 0.83-0.95), DHA was 0.90 (95% CI: 0.85-0.96), and EPA+DHA was 0.93 (95% CI: 0.87-0.99). Methodology The research team began by identifying and including 17 cohorts based on availability of ascertained AF, fatty acid exposures (one or more of EPA, DPA and DHA, and prospective design (cohort or nested case-cohort). The 17 cohort studies comprised 54,799 participants from 21 nations in North America, Europe, Asia and Africa with a mean age of 63 years, of whom approximately one-half were women. Incident AF was assessed using the characteristic findings on standard 12-lead electrocardiogram or event monitors, hospital discharge or outpatient diagnostic codes, or medical record review. To explore for heterogeneity and effect modification, the team prespecified three subgroup analyses, each evaluated within each cohort and then pooled. These included pooling by age (<65 or ≥65 years), by sex (male, female), and among individuals with elevated cardiovascular risk (CV) risk at baseline. Commenting as to why results contrasted with recent meta-analysis of intervention trials, which found high doses (1.8-4 g per day) of omega-3 fatty acid linked to increased AF risk, the authors pointed out that the majority of participants included were community-dwelling individuals who were free of cardiovascular disease (CVD) or at relatively low CV risk. Low supplement use “Second, the prevalence of omega-3 fatty acid supplement use in our cohorts was very low, meaning that biomarker levels of these fatty acids largely reflect habitual dietary intake,” they added. “Moreover, the duration of follow-up in the majority of our cohorts was longer than that for most RCTs [randomized control trials].“ In discussing the modest protective association of omega-3 fatty acid levels with incident AF, the researchers noted that this appeared to be more prominent in phospholipids as compared with cholesterol esters or total plasma. “The reason for this difference is unclear, although it might relate to the larger number of studies in our consortium that assessed fatty acid in phospholipids, which would increase statistical power and precision.” Editorial commentary The significance of the analysis’ findings was the subject of an editorial comment that notes measured omega-3 fatty acid concentrations likely reflect levels achieved through diet, including fish/seafood consumption, and fish oil supplement use was rare (<5%) in almost all cohorts. “In the majority of included studies, EPA+DHA concentrations represented <6% of all lipid compartments assessed, and EPA concentrations represented <1%,” said the editorialists, Christie M. Ballantyne, MD, and Xiaoming Jia, MD, from the Baylor College of Medicine in Houston. “These levels appear to be significantly lower than reported measurements from randomized trials of supplements or prescription strength fish oils.” They also cited studies that find the consistent use of fish oil supplements, even at doses of 1 g per day, likely results in modest though significant increase in AF. Coupled with a potential increased risk for AF, the authors add that current evidence does not support the use of such supplements in CV risk reduction. “In conclusion, based on present evidence, moderate dietary intake of fish and seafood is unlikely to achieve sufficiently high levels of ω-3 fatty acids in blood or tissue that would result in increased AF risk as observed in clinical trials of fish oil supplements and high-dose prescriptions of EPA and EPA+DHA,” they conclude. “Therefore, fish should continue to be an important part of the menu of a heart-healthy diet.” Sources: Qian F, Tintle N, Jensen PN, et al. Omega-3 Fatty Acid Biomarkers and Incident Atrial Fibrillation. J Am Coll Cardiol. 2023;82: 336–349. Ballantyne CM, Jia X. Omega-3 Fatty Acids and Risk for Atrial Fibrillation: Big Fish or Small Fry? J Am Coll Cardiol. 2023;82:350–352. Image Credit: Valeri Luzina – stock.adobe.com