Fish oil supplementation, circulating omega-3 fatty acids, and incident aortic valve stenosis: a propensity score-weighted study in the UK Biobank

Background Aortic valve stenosis is the most common valvular heart disease in ageing populations, yet no pharmacological strategy has been shown to slow its onset or progression. Fish oil supplementation, with its anti-inflammatory and lipid-modifying properties, represents a plausible but untested candidate for prevention. Purpose To examine the association between fish oil supplementation and incident aortic valve stenosis, quantify mediation through circulating fatty acids, and identify subgroups with differential benefit. Methods We conducted a propensity score-weighted cohort study among UK Biobank participants free of prevalent aortic valve stenosis at baseline. Fish oil or omega-3 supplement users were compared with non-users using stabilised inverse probability of treatment weights estimated from 21 baseline covariates. Hazard ratios were obtained from Cox proportional hazards models with robust standard errors. Mediation analysis decomposed the total association of fish oil supplementation with incident aortic valve stenosis through four circulating fatty acid fractions measured by nuclear magnetic resonance spectroscopy. Results Among 501 083 participants followed for a median of 13.8 years (interquartile range 13.0–14.5), 6,561 incident aortic valve stenosis events occurred. After weighting, all covariates were well balanced (maximum standardised mean difference 0.008). Fish oil supplementation was associated with a 10% lower risk of aortic valve stenosis (hazard ratio 0.90, 95% confidence interval 0.86 to 0.95; p<0.001), with weighted incidence rates of 0.92 versus 1.01 per 1 000 person-years. Mediation analysis identified circulating omega-3 fatty acids as the principal mediating pathway, accounting for 18.7% of the total effect (95% confidence interval 7.5% to 42.2%; p<0.001), whereas omega-6, monounsaturated, and saturated fatty acids showed no significant mediation. A significant interaction of fish oil supplementation with prevalent diabetes was observed (p=0.023): participants with diabetes derived a particularly pronounced benefit (hazard ratio 0.76, 95% confidence interval 0.62 to 0.92) compared with those without (hazard ratio 0.92, 95% confidence interval 0.87 to 0.97). Conclusions Fish oil supplementation was associated with a lower risk of incident aortic valve stenosis in this large prospective cohort. Significant mediation through circulating omega-3 fatty acids supports biological plausibility of a causal pathway. The benefit was particularly pronounced among individuals with diabetes. These findings warrant investigation in a randomised controlled trial evaluating omega-3 supplementation for aortic valve stenosis prevention, particularly in high-risk patients.