Neopterin as a Biomarker in Patients with Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension

Abstract

Background: Upregulation of the immune system is regarded to play an important role in the etiopathobiology of pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). To the best of our knowledge, neopterin (NP) has never been investigated in patients with PAH and CTEPH. Objectives: The aim of the study was to evaluate the concentration of NP in blood in order to examine its impact on outcome and relationship with disease severity in that population. Methods: Serum concentration of NP was analysed prospectively in 50 patients (36 with PAH and 14 with CTEPH vs. 31 healthy controls) and assessed in relation to clinical parameters and outcome. Results: NP concentration in the PAH and CTEPH groups combined was significantly higher than in the control group (8.68, 6.39–15.03 vs. 5.14, 4.16–5.98 nmol/L, p < 0.0000001). During 9 months of follow-up, clinical deterioration occurred in 18 patients (including 8 deaths), and NP concentration in this group was higher when compared to stable patients (15.6, 8.52–25.13 vs. 7.87, 6.18–9.89, p = 0.002). The cutoff value of NP derived from ROC curve analysis was 15.3 nmol/L (p = 0.002, AUC 0.77, p = 0.0004, HR = 4.35, 95% CI 1.43–13.18, log-rank test). On Cox regression analysis, NP predicted clinical deterioration (p = 0.009, 95% CI 1.01–1.06). NP correlated positively with NT-proBNP (p < 0.001), red blood cell distribution width (p < 0.001), and right atrium area (p = 0.002) and inversely with 6-min walking test (p = 0.002) and peak oxygen consumption (p = 0.001). Conclusions: NP concentration is increased in patients with PAH and inoperable CTEPH. Elevated NP concentration is associated with adverse clinical outcomes and correlates with clinical parameters.

Prognostic Value of Oxidative Stress Markers in Patients with Pulmonary Arterial or Chronic Thromboembolic Pulmonary Hypertension

“…Recently, we have documented that neopterin concentration which increases the cytotoxic potential of activated macrophages and dendritic cells through promoting oxidative stress was elevated compared to the control group and predicted adverse outcomes in patients with PAH and inoperable CTEPH [38]. The results of another study show that SOD and glutathione peroxidase (GPx) activity are reduced in IPAH lungs, compared to healthy controls [39].…”

Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis—Mechanistic Insights into Anemia of Inflammation and Its Treatment

“…IFN-γ induces neopterin production in macrophages which reflects the extent of cellular immune activation and oxidative stress, and has thus been used as a clinical marker to monitor cellular immune activation in vivo [189]. Elevated serum concentrations of neopterin were associated with a poor outcome and anemia in patients with cancer [25,190], CAD [16], CHF [191] and pulmonary disease [192,193]. IFN-γ further activates indoleamine 2,3-dioxygenase (IDO) thus promoting tryptophan breakdown [194][195][196].…”

Circulating biomarkers in chronic thromboembolic pulmonary hypertension

“…NP may participate in the development of CTEPH via oxidative stress enhancement and act as a potential prognostic biomarker of CTEPH. 44…”