Zaitsev Leonid¹, Takahashi Mio², Noor Ahmed³, Oliveira Camila⁴, Schmid Andreas⁵, Dupont Manon⁶
ABSTRACT:
Background: Heart failure with preserved ejection fraction (HFpEF) is a clinically and pathophysiologically heterogeneous syndrome characterized by diastolic dysfunction, systemic inflammation, and metabolic derangement. Despite its rising prevalence, diagnostic and therapeutic strategies for HFpEF remain limited, in part due to a lack of robust, mechanism-based biomarkers. Emerging lipidomic technologies offer a powerful platform to profile complex lipid species involved in membrane integrity, energy metabolism, and inflammatory signaling, providing novel insight into HFpEF pathobiology. Methods and Results: In this case-control study, targeted and untargeted lipidomic profiling was performed on plasma samples from 120 patients with clinically adjudicated HFpEF and 80 matched controls using high-resolution mass spectrometry. Over 600 lipid species were identified and quantified across key subclasses, including sphingolipids, phospholipids, ceramides, and acylcarnitines. Multivariate analysis revealed a distinct lipidomic signature in HFpEF characterized by elevated levels of ceramide (d18:1/16:0), lysophosphatidylcholine (LPC 18:2), and acylcarnitine C18:1, all of which were associated with impaired diastolic parameters, reduced exercise capacity, and elevated NT-proBNP. Pathway enrichment implicated dysregulated fatty acid β-oxidation, altered membrane remodeling, and activation of pro-inflammatory lipid mediators. Receiver operating characteristic (ROC) analysis demonstrated high diagnostic accuracy for composite lipid panels, with AUC values exceeding 0.89. Key biomarkers were independently associated with HFpEF status after adjustment for clinical confounders, and correlated with echocardiographic markers of left atrial pressure and myocardial stiffness. Conclusion: Lipidomic profiling reveals a novel molecular fingerprint of HFpEF, uncovering candidate biomarkers that reflect the metabolic and inflammatory dimensions of the disease. These findings support the integration of lipidomics into biomarker discovery pipelines for improved HFpEF diagnosis, risk stratification, and therapeutic targeting in precision heart failure care.