Proinflammatory Lipids in Sickle Cell Disease-Associated Pulmonary Hypertension.
Authors: Ataga Kenneth I. , Hillery Cheryl A. , Park Hyeon A. , Moore Charity G. , Jones Susan , Wang Jingli , Hinderliter Alan , Pritchard Kirkwood A. 
Published: April 2020

Abstract
Introduction: Pulmonary hypertension (PHT) occurs commonly in patients with sickle cell disease (SCD). The pathogenesis of PHT in this setting is likely multifactorial. There is an abundance of evidence suggesting that SCD is characterized by a chronic inflammatory state. In addition, we have recently reported that SCD patients with PHT exhibit higher levels of inflammatory markers compared to those SCD patients without PHT. The purpose of this study is to determine whether proinflammatory lipids are associated with PHT in SCD.
Methods: A cohort of patients followed at the Sickle Cell Clinic at UNC-Chapel Hill was evaluated in this cross-sectional study. Doppler echocardiography was used to determine the pulmonary artery systolic pressure (PASP). Pulmonary hypertension was subsequently defined using an age-, sex- and BMI-adjusted reference range. Lipid profiles, including total cholesterol, triglyceride and high-density lipoprotein (HDL) were measured, and low-density lipoprotein (LDL) levels were calculated using the Friedewald formula (LDL = Total cholesterol - Triglyceride/5 - HDL) in all SCD patients and controls subjects without SCD. To determine the levels of proinflammatory HDL, we measured the rates of fluorescence intensity of dichlorofluorescein (DCF) over 2 hours following its addition to an HDL aliquot. Nonparametric tests (α = 0.05) were used to compare median values in SCD patients with (PHT) and without PHT (no PHT) as well as control individuals.
Results: Seventy-one patients with SCD, 24 of whom had PHT (33.8%), and 12 healthy, control subjects (African-Americans and Caucasians) were evaluated. Compared with controls, both SCD patients with and without PHT had lower total cholesterol levels (PHT 96.8 mg/dL, no PHT 106.3 mg/dL, control 133.4 mg/dL; p = 0.004) and LDL levels (PHT 34.6 mg/dL, no PHT 43.6 mg/dL, control 63.6; p = 0.009). In addition, SCD patients with and without PHT had higher levels of proinflammatory HDL (presented as slopes of the increase in DCF fluorescence over time) than control subjects (PHT 4.06 FU, no PHT 3.41 FU, control 2.37 FU; p = 0.0001). However, no significant differences in HDL or triglyceride levels were observed when all three groups were compared. Finally, when SCD patients with PHT were compared only to SCD patients without PHT, median levels of proinflammatory HDL were higher (p = 0.03), although the difference was only of borderline statistical significance when corrected for multiple comparisons (α = 0.05/3 = 0.0167). No significant differences in the other measured variables were observed when only SCD patients with and without PHT were compared.
Conclusion: Although patients with SCD have lower levels of total cholesterol and LDL compared to healthy control subjects, they exhibit higher levels of proinflammatory HDL. Furthermore, median levels of inflammatory lipids appear to be higher in SCD patients with PHT compared to those patients without this complication. These findings confirm the inflammatory nature of SCD and further suggest a contribution of inflammation to the pathogenesis of PHT in these patients. While proinflammatory HDL is hypothesized to predispose to atherosclerosis in the general population, the occurrence of this complication is thought to be low in SCD patients. Further studies are required to determine the significance of increased inflammatory lipids in SCD and their contribution to the pathogenesis of PHT in SCD.