Metabolites of the kynurenine pathway can help predict disease severity, response to treatment, and survival in patients with pulmonary arterial hypertension (PAH), according to a new study published in Scientific Reports. This knowledge could help scientists develop new treatment strategies for the disease in the future.

It was already known that the kynurenine pathway is activated in patients with PAH being treated for their disease. 

Here, a team of researchers led by Daphne Merkus, PhD, from the Department of Cardiology, Erasmus MC, University Medical Center in Rotterdam, Netherlands assessed the kynurenine pathway metabolism in patients with PAH who have never been treated before to investigate its prognostic values as well as the effect of PAH therapy.


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The researchers measured the levels of kynurenine pathway metabolites in the plasma of 43 patients with PAH who have never been treated and 111 healthy volunteers. Of the 43 patients, 39 were prescribed PAH-targeted therapies after the diagnosis. The researchers also measured the levels of the metabolites 6 months and 1 year after the initiation of treatment.

Read more about the treatment of PAH

The results showed that the levels of tryptophan were lower while that of kynurenine, 3-hydroxykynurenine, quinolinic acid, kynurenic acid, and anthranilic acid were higher in patients with PAH who have never been treated compared to healthy controls, suggesting that the kynurenine pathway was activated.

The researchers also reported that Increased kynurenine pathway metabolites correlated with higher pulmonary vascular resistance, shorter 6-minute walking distance, and worse functional class. Moreover, increased levels of kynurenine, 3-hydroxykynurenine, quinolinic acid, and kynurenic acid measured 1 year after the initiation of treatment were associated with worse long-term survival.

The researchers then conducted some experiments where they exposed human lung primary cells grown in the laboratory to different cytokines. They found that the different types of cells showed a similar kynurenine pathway-metabolite profile as in patients with PAH following exposure to interleukin-6/IL-6 receptor α complex.

The researchers concluded that the activation of the kynurenine pathway metabolism was likely mediated by interleukin-6 signaling.

Reference

Cai Z, Tian S, Klein T, et al. Kynurenine metabolites predict survival in pulmonary arterial hypertension: a role for IL-6/IL-6Rα. Sci Rep. 2022;12:12326. doi:10.1038/s41598-022-15039-3