Abstract Body: Background Heart failure with preserved ejection fraction (HFpEF) presents with clinical heterogeneity and accounts for 50% of heart failures cases with limited clinical interventions. Inhibition of lysophosphatidic acid (LPA), a bioactive lipid, produced by autotaxin (ATX) reduces cardiac inflammation and prevents cardiac remodeling during acute myocardial infarction, however, its role in HFpEF remains unanswered.

Methods To understand the role of bioactive lipids in a retrospective case-control HFpEF study, plasma samples from patients (n=210) and healthy control (n=27) were subjected to mass spectrometry and multiplex ELISA based assay. HFpEF in 12-weeks-old C57BL/6J mouse (n=30) was developed through combined administration of high-fat diet (HFD, 60% of calories from lard-based diet) and Nw-Nitro-L-arginine methyl ester (L-NAME, 0.85 g/L). HFpEF phenotype was confirmed at week-5 through echocardiography, intraperitoneal glucose tolerance test (1g/kg body weight), and blood pressure via tail-cuff methods and data was compared with control mice under chow diet. Autotaxin was inhibited using daily oral gavage of PF8380 (30 mg/kg body weight) for another 10-weeks.

Results Our findings indicates that HFpEF patients have significantly higher level of systemic inflammation with female HFpEF harboring even higher pro-inflammatory and membrane-destabilizing lipid signatures compared to male. Both sexes showed an elevation of LPE/LPC and ether-lined species (LPE-O, PC-O). Female HFpEF patients reflect higher lipid remodeling amplified by comorbidities such as hypertension and type 2 diabetes mellitus (T2DM) and upregulation of PS38:4, LPE O-16:1, LPE O-18:2, PC 36:4;0. Female patients have higher number of significant lipids than male. HFpEF patients also had a significantly higher level of inflammatory markers compared to control (all P<0.001). Five weeks of HFD+L-NAME in C57BL/6J mice increased systolic and diastolic blood pressure (both P<0.001), E/A, E/e’ ratios (P<0.01), LV mass (P<0.001) and isovolumic relaxation time (P<0.001) compared to Chow and reduced tolerance to glucose (P<0.05) with no change in ejection fraction. 10-weeks of PF8380 reduced the indices of HFpEF compared to vehicle group and reduced cardiac fibrosis compared to vehicle group (all P<0.05).

Conclusion Our findings identify LPA as potential driver of HFpEF irrespective of species that can be neutralized by PF8380 rendering therapeutic potential and therefore of clinical value.