Increased Xanthine Oxidoreductase Activity in Patients With Systemic Sclerosis-Associated Pulmonary Arterial Hypertension

Abstract

Background

Preclinical studies have demonstrated the importance of xanthine oxidoreductase (XOR) in the pathobiology of pulmonary hypertension (PH) through generation of uric acid, reactive oxygen species, and vascular endothelial dysfunction.

Research Question

In 2 well-characterized cohorts of patients with systemic sclerosis (SSc), what is the relationship of systemic XOR enzymatic activity to PH diagnosis, development, and severity?

Study Design and Methods

Serum samples from 48 patients with systemic sclerosis-associated pulmonary hypertension (SSc-PH) were assayed for XOR activity using an enzyme-linked immunosorbent assay (ELISA) in a discovery cohort from the Johns Hopkins Pulmonary Hypertension Program, including 12 index treatment-naive patients with samples collected before and after 36 weeks of PH-specific therapy. Sixty-nine patients with SSc-PH were compared with patients with SSc without PH in a second cohort from the Johns Hopkins Scleroderma Center using a nested case-control design. Patients in the Johns Hopkins Scleroderma Center cohort were under longitudinal surveillance for development of right heart catheterization-confirmed PH, which allowed for serum collection at proximate and distant time points before PH diagnosis (1 proximate sample within 12 months of PH diagnosis and 1 distant sample within 5 years of PH diagnosis, with a minimum 6-month separation between samples).

Results

XOR activity temporally correlated with SSc with pulmonary arterial hypertension disease development, and increasing XOR activity over the time preceding PH diagnosis was associated with worse disease severity by invasive hemodynamics. In a small subset of patients, XOR activity increased after initiation of PH-specific therapy.

Interpretation

Taken together, these results suggest increased XOR activity and hyperuricemia may represent modifiable risk factors in SSc-PH.