Since uric acid (UA) levels in patients with idiopathic pulmonary arterial hypertension (iPAH) are associated with an impaired clinical and hemodynamic profile, they may serve as a useful noninvasive indicator of disease severity in these individuals, according to the results of an analysis published in the European Respiratory Journal.

Researchers conducted a translational study in a French Pulmonary Hypertension Network (FPHN) registry of patients with iPAH, heritable PAH (hPAH), or anorexigen-associated PAH to analyze the prognostic effect of circulating UA in the management of patients with PAH, as well as to determine whether UA and its voltage-driven urate transporter 1 (URATv1) contribute to pulmonary vascular remodeling in those with PAH. Serum UA levels were established in individuals with iPAH, hPAH, or anorexigen-induced PAH at baseline and during follow-up in the FPHN registry.

Incident, treatment-naive patients with iPAH, hPAH, or anorexigen-induced PAH who were recorded in the FPHN registry between January 1, 2006, and March 30, 2016, were reviewed retrospectively and enrolled in the study if a dosage of circulating UA was available at baseline and/or at the time of first follow-up. Protein levels of xanthine oxidase (XO) and the URATv1 transporter were evaluated in the lungs of patients with PAH and normal control individuals, as well as in monocrotaline (MCT) and sugen/hypoxia (SuHx) rats. Additionally, functional studies were conducted with the use of human pulmonary artery smooth muscle cells (PA-SMCs) and 2 animal models of pulmonary hypertension (PH).

Overall, a total of 330 incident patients were identified — 238 with iPAH, 38 with hPAH, and 54 with anorexigen-induced PAH — and were enrolled in the French registry. These participants had both a baseline measurement of UA and a baseline evaluation, which included right heart catheterization, 6-minute walking distance (6MWD), and World Health Organization/New York Heart Association functional class. A total of 163 patients underwent a reevaluation of their PAH within 1 year following diagnosis, along with serum UA measurement. The median time between baseline and the initial reevaluation was 4.4 months. At first follow-up, the median UA level was 8.3 mg/dL in men and 6.8 mg/dL in women.


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Patients with high serum UA levels at the time of PAH diagnosis had a significantly higher body mass index, more frequent diabetes diagnoses, and significantly lower

6-MWD values (P =.03, P =.007, and P =.005, respectively). At first reevaluation, participants with high levels of UA were significantly older and more frequently had diabetes and hypertension (P =.01, P <.001, and P =.001, respectively). Further, 6-MWD was significantly lower among individuals with persistently high serum UA levels (P =.001). 

Results of the study showed that high UA serum levels were linked to a poor prognosis at initial follow-up but not at baseline. Both the generating enzyme XO and URATv1 were upregulated in the wall of remodeled pulmonary arteries in patients with iPAH, as well as MCT and SuHx rats. In fact, high UA levels promote a mild increase in cell growth in PA-SMCs in patients with iPAH, but not in the PA-SMCs of control individuals. Further, oxonic acid-induced hyperuricemia did not aggravate MCT-induced PH in rats. Chronic benzbromarone treatment of MCT and SuHx rats mildly lessened pulmonary vascular remodeling.

The investigators concluded that UA concentration is increased in patients with PAH and is associated with survival following the initiation of PAH treatment. The metabolism of UA is disturbed in remodeled pulmonary vascular walls in both human and experimental PAH.

Reference

Savale L, Akagi S, Tu L, et al. Serum and pulmonary uric acid in pulmonary arterial hypertension. Eur Respir J. Published online January 14, 2021. doi: 10.1183/13993003.00332-2020.