Autotaxin Inhibition Ameliorates HFpEF Phenotype By Reducing LPA-Mediated Systemic Inflammation and Cardiac Remodeling
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
HFpEF accounts for roughly half of heart failure admissions and lacks disease-modifying therapy. Autotaxin (ENPP2) generates lysophosphatidic acid (LPA), a profibrotic and pro-inflammatory bioactive lipid. Whether circulating lysophospholipid metabolism is altered in HFpEF, and whether autotaxin inhibition modifies an established experimental HFpEF phenotype, is untested.
Methods
Plasma from patients with HFpEF (n=210) and non-heart-failure comparators (n=27) underwent untargeted and LPA-targeted mass spectrometry and a nine-analyte multiplex immunoassay. Male C57BL/6J mice received a high-fat diet plus L-NAME (0.85 g/L) or chow for 5 weeks; after phenotype confirmation, they received oral PF-8380 (30 mg/kg/day) or vehicle for 10 weeks. Endpoints were echocardiography, functional assessment, gravimetric studies, tail-cuff pressure, trichrome fibrosis, and flow cytometry of heart and spleen.
Results
All nine analytes, including the autotaxin protein ENPP2, were higher in HFpEF than comparators. HFpEF plasma showed higher LPE O-16:1, LPE O-18:2, PS 38:4 and PC 36:4;O, and lower SM 39:2;O3 and PS 36:0. LPA 20:0 was 3.5-fold higher in both sexes, whereas LPA 18:2 was lower in women. Diet plus L-NAME raised blood pressure, LV mass, and isovolumic relaxation time with preserved ejection fraction. PF-8380 reduced echocardiographic indices of diastolic dysfunction, fibrosis area, cardiomyocyte area, and cardiac CD11b+, CD64+, CD86+, and Ly6G+ frequencies, without a change in fat or lean mass.
Conclusion
In male mice with established two-hit HFpEF, autotaxin inhibition improved diastolic indices and reduced fibrosis, hypertrophy and cardiac myeloid accumulation. Human data show altered lysophospholipid composition. Collectively, these findings nominate the autotaxin–LPA axis as a tractable therapeutic target and support further evaluation of autotaxin inhibition as a candidate disease-modifying strategy for HFpEF management.
