Abstract
Background: Slit ligand guidance 2 (Slit2) is a ligand of the Roundabout guidance receptor (ROBO4), a transmembrane endothelial-specific receptor expressed in lung tissue. Pulmonary vascular remodeling contributes to PAH development and ROBO4 has been shown to play a role in inhibiting VEGF related angiogenesis. No studies have evaluated ROBO4 and Slit2 levels in PAH. Research Question: This study sought to assess if ROBO4 and/or Slit2 levels are detectable, altered in and associated with survival outcomes and hemodynamic measurements in patients with PAH. Methods: Serum ROBO4 levels were measured in 139 adults with PAH and 90 controls. Serum Slit2 levels were measured in 210 adults with PAH and 40 controls. Mann-Whitney U tests were used to compare biomarker levels in PAH and controls. Biomarker levels in the PAH cohort were compared to hemodynamic measurements and survival analyses were conducted for a composite outcome (death or transplant) using Cox proportional hazard models, and Kaplan Meier analysis with biomarkers dichotomized at the median. Results: ROBO4 and Slit2 levels were higher in PAH vs control patients (p=0.0005, p=0.002). In Kaplan-Meier analysis, ROBO4 and Slit2 levels above the median were associated with time to death or transplant (Logrank test p=0.016, p=0.03). ROBO4 and Slit2 levels were positively associated with death or transplant using Cox proportional regression, adjusted for age with a hazard ratio of 1.8 (95% CI 1.07-2.97, p=0.003) and 1.49 (95% CI 1.11-1.99, p=0.008), respectively. There were no statistically significant associations between ROBO4 and Slit2 levels and hemodynamic data such as mPAP, mRAP and PVR. Conclusions: This pilot data demonstrates that the angiogenic protein Slit2 and its receptor ROBO4 levels are both associated with survival outcomes in PAH. Future studies should evaluate in vitro studies to localize Slit2/ROBO4 in lung tissue using immunohistochemistry.
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