HPLC Profiling of Oxylipins Highlights 15-Keto PGF2α as a Potential Prognostic Marker in Heart Failure

Researchers from the University of Toledo College of Medicine and Life Sciences (Toledo, Ohio) and Wayne State University (Detroit, Michigan) tested whether a panel of oxylipins could predict and stratify mortality risk in patients with heart failure with preserved ejection fraction (HFpEF). They used high-performance liquid chromatography (HPLC) to extract polyunsaturated fatty acyl (PUFA) metabolites from serum samples. The study was published in ESC Heart Failure (1).

Associated with significant morbidity and mortality, several disease states are linked with HFpEF, such as obesity and diabetes; both are known to instigate and spread systemic inflammation (2-4). Recent research has been concentrating on oxidized polyunsaturated fatty acyl (PUFA) lipids in cardiovascular inflammation. These oxidized PUFA lipids, called oxylipins, are bioactive metabolites that regulate inflammation, vascular tone, angiogenesis, and platelet aggregation (5). In addition, oxylipins modulate pro-inflammatory, anti-inflammatory and pro-resolutory immune responses through cytokine signaling, leukocyte recruitment and multi-system inflammasome activation (6). Recent studies have revealed that dietary supplementation with PUFAs might augment cardiorespiratory performance through anti-inflammatory effects in obese patients with HFpEF (7). While xylipins have been well studied in diseases associated with HFpEF, and have been implicated in vascular injury, atherosclerosis and calcificationthe prognostic importance of oxylipins in HFpEF is not well characterized (8).

Venous and arterial blood samples were collected during right heart catheterization from 90 HFpEF patients at a single institution. Patients were followed for five years to determine morbidity and mortality rates. The team measured 143 arterial and 143 venous oxylipins in all study participants using liquid chromatography-mass spectrometry (LC-MS). Volcano plots were used to visualize differences in oxylipins between survived and deceased groups. Receiver operator characteristic (ROC) curves were used to determine optimal biomarker cut-points, and the relationship between the most significant oxylipins and mortality was assessed with Kaplan-Meier (KM) curves. It was found that HFpEF patients with 5-year mortality had increased age, decreased body mass index, decreased diastolic blood pressure and worse renal function at baseline, as well as more severe pulmonary hypertension (PH) and right heart dysfunction. Volcano plot analysis revealed that arterial oxylipin 15-keto prostaglandin F2a (PGF2a) was significantly associated with 5-year mortality. ROC curve analysis identified an optimal cut-point for 15-keto PGF2a, and participants with elevated arterial 15-keto PGF2a had significantly increased 5-year mortality on KM curves. Multivariable adjusted analysis identified 15-keto PGF2a as a significant predictor of 5-year mortality (OR 1.82; CI 1.03, 3.5) (1).

For this cohort of patients with HFpEF, arterial 15-keto PGF2a, a stable metabolite of PGF2a, significantly predicted 5-year mortality. The findings provide preliminary evidence that circulating oxylipins may be involved in the pathogenesis and prognosis of HFpEF. If confirmed by larger cohort studies, the arterial levels of PGF2a may not only serve as a prognostic marker of HFpEF but also offer therapeutic opportunities targeting FP receptor signaling (1).

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References

1. Aradhyula, V.; Manandhar, S.; Sherafati, A. et al. Circulating Oxylipins Predict Mortality in Heart Failure with Preserved Ejection Fraction. ESC Heart Fail. 2025.DOI: 10.1002/ehf2.15425
2. Paulus, W. J.; Tschöpe, C. A Novel Paradigm for Heart Failure with Preserved Ejection Fraction: Comorbidities Drive Myocardial Dysfunction and Remodeling Through Coronary Microvascular Endothelial Inflammation. J. Am. Coll. Cardiol. 2013, 62 (4), 263-271. DOI: 10.1016/j.jacc.2013.02.092
3. Packer, M.; Lam, C. S. P.; Lund, L. H. et al. Characterization of the Inflammatory-Metabolic Phenotype of Heart Failure with a Preserved Ejection Fraction: A Hypothesis to Explain Influence of Sex on the Evolution and Potential Treatment of the Disease. Eur. J. Heart Fail. 2020, 22, 1551-1567. DOI: 10.1002/ejhf.1902
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7. Carbone, S.; Billingsley, H. E.; Canada, J. M. et al. Unsaturated Fatty Acids to Improve Cardiorespiratory Fitness in Patients with Obesity and HFpEF: The UFA-Preserved Pilot Study. JACC Basic Transl. Sci. 2019, 4, 563-565. DOI: 10.1016/j.jacbts.2019.04.001
8. Cheng, H. M.; Wang, J. J.; Chen, C. H. The Role of Vascular Calcification in Heart Failure and Cognitive Decline. Pulse (Basel) 2018, 5, 144-153. doi:10.1159/000484941