Abstract
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a prevalent syndrome with limited diagnostic and therapeutic options. Dyslipidaemia is a common comorbidity, and signalling lipids, bioactive molecules regulating key pathophysiological processes, are implicated in HFpEF, though their relationships remain unclear. METHODS: Plasma samples from the PREVEND cohort were analysed, including 172 control samples, 125 PreDx-HFpEF samples (before diagnosis), and 30 PostDx-HFpEF samples (after diagnosis, paired with PreDx-HFpEF). A total of 261 signalling lipids were profiled via LC-MS/MS. Additionally, sums and ratios of specific signalling lipid targets were calculated. Cox proportional hazards and logistic regression models were performed to identify relationships between signalling lipids and HFpEF progression. FINDINGS: PreDx-HFpEF individuals showed elevated non-esterified oxylipins (derived from DHA, AA, EPA) and specific lysophospholipids, compared with controls, and these signalling lipids emerged as potential predictors of incident HFpEF. In contrast, the PostDx-HFpEF subgroup demonstrated an attenuation of non-esterified oxylipins and lysophospholipids compared with control and PreDx-HFpEF samples, although findings are exploratory given the limited sample size. Among 103 detected non-esterified oxylipins, 44 showed significant associations with HFpEF-related outcomes. Together with 18 additional signalling lipids, this yielded 62 significant signalling lipids, 68% of which were independent of high-density lipoprotein (HDL). INTERPRETATION: Selected signalling lipids provide predictive information prior to HFpEF diagnosis, whereas post-diagnostic lipid alterations reflect disease-associated metabolic changes and should be interpreted cautiously. These findings highlight the potential relevance of signalling lipids in HFpEF. FUNDING: This study was funded by Netherlands Heart Foundation, Chinese Scholarship Council, and Dutch Research Council.