Autotaxin Inhibition Ameliorates HFpEF Phenotype By Reducing LPA-Mediated Systemic Inflammation And Cardiac Remodeling
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:…
Heart failure with preserved ejection fraction (HFpEF) is a common condition that accounts for about half of heart failure admissions. Currently, there are no therapies that modify the disease. Autotaxin (ENPP2) is an enzyme that produces lysophosphatidic acid (LPA), a substance linked to fibrosis and inflammation. It is unknown if the metabolism of lysophospholipids is different in HFpEF patients and if inhibiting autotaxin can change the disease in a mouse model. This study examines these questions.
Researchers analyzed blood plasma from 210 HFpEF patients and 27 healthy individuals. They used mass spectrometry and a blood test for nine different markers. Mice were fed a high-fat diet with LNAME or regular food for five weeks. Afterwards, they received a drug called PF-8380 or a placebo for 10 weeks. The researchers measured heart function, overall health, body weight, vascular pressure, liver tissue, and immune cells in the heart and spleen.
The analysis revealed that all nine markers, including ENPP2, were higher in HFpEF patients than in controls. The plasma of HFpEF patients contained higher levels of LPA O16:1, LPA O18:2, PS 38:4, and PC 36:4:O, while levels of SM 39:2; O3 and PS 36:0 were lower. LPA 20:0 was three and a half times higher in both sexes, but LPA 18:2 was lower in women. HFpEF patients also had elevated blood pressure, larger left ventricular mass, and longer isovolumic relaxation time, but their hearts continued to pump blood effectively.
When the mice were given PF-8380, they had improved diastolic heart function, lower fibrosis area, smaller cardiomyocyte area, and fewer immune cells in the heart, without changes in fat or lean body mass. These findings in mice suggest that inhibiting autotaxin could be a potential treatment for HFpEF, improving its symptoms and reducing its severity.
The increased levels of lysophospholipids in humans also support this idea. Further research is needed to determine if autotaxin inhibition could be a viable strategy for managing this common heart condition.
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