Alveolar and Bronchial Nitric Oxide Parameters in Pre-Capillary Pulmonary Hypertension

Background: Exhaled NO concentrations at different flow rates can be used to calculate pulmonary NO dynamics in the conductive and peripheral airways and can be described by the total bronchial flux of NO (JawNO) and alveolar NO concentration (CANO), respectively. Changes in these parameters have been shown in pre-capillary pulmonary hypertension (PH); however, data from studies with low sample sizes are controversial and did not prospectively assess JawNO and CANO after adequate therapy. Methods: Patients with untreated pre-capillary PH (group 1: N = 23, group 3: N = 11, group 4: N = 18) and control subjects (N = 27) were recruited in a single-center observational study. Patients with group 1 (N = 15) and group 4 PH (N = 13) also attended a single follow-up visit when on pulmonary vasodilators or following interventions. Exhaled NO concentrations were measured at 50 mL/s and 100-250 mL/s expiratory flows and the two-compartment linear model was used for the calculation of JawNO and CANO. Results:CANO was higher in patients (median (interquartile range) 3.84 (2.64-7.29) ppb) than in control subjects (2.70 (1.85-4.29) ppb, p < 0.01; Mann-Whitney test) without a difference among PH groups or an association with survival. CANO showed moderate negative associations with the diffusion capacity of the lung for carbon monoxide (Spearman r = -0.41, p < 0.01) and a trend for mortality risk categories in groups 1 and 4 (r = -0.30, p = 0.06). Only JawNO changed at follow-up (0.69 (0.14-1.10) vs. 0.91 (0.40-1.68) nL/s, p = 0.02; Wilcoxon test), and there was a positive correlation between its increase and the improvement in 6 min walk distance (r = 0.40, p = 0.04). Conclusions: Alveolar NO concentration is increased in patients with pre-capillary PH, and the change in JawNO is related to the improvement in exercise capacity in PH groups 1 and 4. This is the first study implying that JawNO might be a non-invasive marker responsive to improved pulmonary hemodynamics in PH.