Physical activity modifies the association between lipidomic risk markers and heart failure in a population-based cohort

Background Heart failure (HF) represents a major global health burden. While traditional risk factors are used for risk stratification, they may not fully capture the metabolic pathways involved in HF development. Ceramide (Cer) and phosphatidylcholine (PC) lipidomic biomarkers have emerged as indicators of cardiometabolic risk. However, the relationship between habitual physical activity, lipidomic profiles, and HF risk remains incompletely understood. Purpose To investigate the associations between habitual physical activity, circulating Cer–PC lipidomic biomarkers, and both prevalent and incident HF in a population-based cohort. Methods We analysed data from 7,722 participants in a population-based cohort. Physical activity was assessed by questionnaire and categorised as low, moderate, or high. Associations with prevalent HF (n=157) were evaluated using multivariable logistic regression. Incident HF events (n=584) were analysed using subgroup-specific Cox proportional hazards models with age as the underlying time scale and stratification by sex. Results Higher physical activity was associated with more favourable lipidomic profiles, including lower CERT1 and CERT2 scores and reduced concentrations of several long-chain ceramide species (all p<0.001). In prevalent HF analyses, ceramide-based ratios showed the strongest adjusted associations. For incident HF, lipidomic risk markers were most strongly associated with HF among participants with low physical activity, including CERT2 (adjusted HR 1.36, 95% CI 1.14–1.62; p=0.001) and Cer(d18:1/16:0) (adjusted HR 1.33, 95% CI 1.11–1.59; p=0.002). In the moderate activity group, most associations attenuated, except for an inverse association for PC(14:0/22:6) (adjusted HR 0.88, 95% CI 0.77–0.99; p=0.039). In the high activity group, CERT2 remained independently associated with HF risk (adjusted HR 1.40, 95% CI 1.04–1.89; p=0.027). Conclusion Habitual physical activity is associated with favourable Cer–PC lipidomic profiles and appears to modify the relationship between lipidomic biomarkers and HF risk across physical activity strata.