Low circulating lysophosphatidylcholine and phosphatidylcholine are linked to pulmonary hypertension severity

Abstract

Background: Pulmonary hypertension (PH) is a progressive pulmonary vascular disease. Given the mechanistic role of lipids in peripheral vascular diseases, we hypothesized that PH is also associated with pathologic circulating lipid metabolites. To test this, lipid metabolites of patients with PH were evaluated in association with clinical severity, including right ventricle systolic pressure (RVSP), pulmonary vascular resistance (PVR), right ventricular size and function, and plasma endothelin-1. Methods and Results: Participants were recruited as a part of a small site clinical trial (Clinicaltrials.gov, # NCT01586156). Comprehensive lipidomes were determined using unbiased nontargeted lipidomics (Metabolon Inc., Durham, NC) in 30 PH patients and 12 healthy controls. RVSP, right ventricular end diastolic (RVED) and end systolic (RVES) area were measured by echocardiogram and PVR was calculated. Plasma endothelin-1 was measured by Elisa. Nontargeted analysis detected 1099 lipid-related metabolites of which 83 and 60 metabolites were upregulated and downregulated in PH ( p<0.05), respectively. Pathway enrichment analysis identified abnormalities of lipid metabolic pathways including choline-related, acylcarnitine, and sphingolipid metabolism. Targeted measures of lysophosphatidylcholine (lysoPC) and phosphatidylcholine (PC) confirmed these findings. Total circulating lysoPC and PC were downregulated [Healthy vs. PH, mean ± SD, mM; LysoPC, 786±102 vs. 586±139, p<0.01; PC, 1855±389 vs. 1495±282, p<0.01]. Sixteen out of the 25 lysoPC detected, and 25 out of 39 PC detected, were lower in PH, including the most abundant lysoPC-16:0 [226±31 vs. 186±39, p<0.01] and PC-34:2 [436±91 vs. 360±75, p<0.01]. RVSP, PVR, RVED area, RVES area and endothelin-1 were all higher in PH (all, p<0.01). Lipid metabolites were inversely related to clinical measures of PH severity. For example, lysoPC-20:3 was related to RVSP [ r=−0.63, p<0.01], PVR [ r=−0.50, p<0.01], and endothelin-1 [ r=−0.51, p<0.01], and PC-36:5 was inversely related to RVSP [ r=−0.36, p=0.02], PVR [ r=−0.43, p<0.01], and endothelin-1 [ r=−0.50, p<0.01]. Additionally, both lysoPC-20:3 and PC36:5 metabolites were inversely associated with right ventricular size, measured as RVED area [lysoPC-20:3, r=−0.62, p<0.01; PC-36:5, r=−0.69, p<0.01], RVES area [lysoPC-20:3, r=−0.66, p<0.01; PC-36:5, r=−0.71, p<0.01] and related with RV systolic function, measured as RV fractional area change [lysoPC-20:3, r=0.57, p<0.01; PC-36:5, r=0.50, p<0.01). Conclusion: Plasma phosphatidylcholine is low in PH and is associated with disease severity, suggesting disturbances in PC metabolism are important in pulmonary vascular disease. NIH NHLBI R37HL60917, R01HL115008 CTSA UL1TR000439; UL1TR002548. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.