Abstract P3103: Circulating and tissue levels of omega-3 fatty acids and incident peripheral artery disease: an individual participant-level pooled analysis of prospective studies

Background: Evidence from observational studies and randomized trials suggest a favorable role of omega-3 fatty acids on cardiovascular outcomes. However, whether omega-3 fatty acids may reduce the incidence of peripheral artery disease (PAD) is not known. Aims: We prospectively evaluated blood and adipose tissue levels of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), and the sum of EPA and DHA, with respect to incident PAD. Methods: We included 11 prospective studies from a global consortium up to May 2023 with measurements of ALA, EPA, DPA, or DHA (as a % of total fatty acids) in blood or adipose tissue among adults (age≥18), who were free of coronary artery disease, stroke, and PAD at baseline, and assessed incident PAD events. Each cohort conducted de novo individual-level analyses with a prespecified analytical plan and harmonized definitions for exposures, outcomes, covariates (including demographics, cardiovascular risk factors, medication use, and omega-6 fatty acid levels), and subgroups. Pooled hazard ratios (HRs) were calculated using inverse-variance weighted meta-analysis. Results: Among 142,316 participants from North America, Europe, and Australia followed for a weighted median of 13.7 years (range of median follow-up: 9.8 to 26.2 years), 1,842 incident cases of PAD were ascertained. In multivariable-adjusted pooled analysis, very long-chain EPA, DPA, DHA, and EPA+DHA each associated with lower PAD incidence, with HRs (95% CI) per interquintile range of 0.79 (0.69, 0.91), 0.80 (0.68, 0.95), 0.74 (0.64, 0.85), and 0.79 (0.69, 0.90), respectively ( P <0.01 for each) ( Figure 1 ). Long-chain ALA was not associated with PAD, 1.14 (0.98, 1.33). Heterogeneity between studies was low to moderate ( I 2\ ranging from 0% to 57%). Results were broadly consistent in prespecified subgroups by age, sex, smoking status, prevalent diabetes, and biomarker lipid fraction. Conclusion: In this large international consortium, objective levels of very long-chain, but not long-chain, omega-3 fatty acids inversely associated with incident PAD. Our data suggest a protective role for very long-chain omega-3 fatty acids in the development of PAD, supporting the need for further mechanistic studies and appropriately powered randomized controlled trials.