This is the first longitudinal study to describe the changes in gas transfer in PAH over time. Lung diffusing capacity for NO, but not CO, dropped due to the disproportionate loss of membrane diffusion, Dm, as compared to changes in the vascular bed available for gas exchange, Vc. These findings suggest that the efficiency of the alveolar-capillary unit in PAH worsens over time independent of traditional clinical and echocardiographic measures. The results also put forward the potential utility of DLNO in tracking progression of disease in PAH.
As in prior work, DL was reduced in PAH patients. Although PAH patients and controls were not well matched by age and gender, the decrease in DL is not likely explained by age and gender alone. Earlier studies measured DLCO at two different oxygen concentrations and calculated Dm and Vc except for the study by Borland et al. where the single breath test measuring both CO and NO uptake was used. All discovered a decrease in DL, but earlier studies showed predominant loss of Vc while more recent ones showed that Dm is reduced out of proportion to Vc. The difference between earlier studies and more recent ones could be attributed to differences in techniques or use of pulmonary vasodilators leading to higher measured Vc. In this study, the single breath technique measuring DLNO and DLCO was used to assess Dm and Vc. Dm was reduced proportionally to Vc in patients with PAH, and thus Dm/Vc was not different from controls. This confirms the interdependence of Dm and Vc in pulmonary vascular diseases and any change in the vascular bed that reduces Vc would lead to a reduction in Dm through a reduction in the surface area available to gas exchange.
In PAH, the reduction in Vc is likely multifactorial: increased pulmonary vascular resistance, decreased cardiac output and local thrombosis of the vascular bed. Mechanisms underlying the reduced Dm may include an increase in the alveolar-capillary membrane thickness caused by fibrotic or proliferative process, and/or interstitial edema. Of note, none of the patients recruited for the study had interstitial lung disease. The decreased DL in association with decreased Dm and Vc has been described in chronic heart failure patients in stable clinical condition . There is growing evidence that as disease progresses; the left ventricular function may become independently compromised in PAH [19, 20]. This may contribute to the reduced DL, Dm and Vc.
Over time, the increase in Vc in association with a decrease in Dm could be explained by the effect of vasodilator therapy on the diseased pulmonary vasculature. Dm would not be expected to increase proportionally to Vc with vasodilation alone as the thickened alveolar-capillary membrane is not affected and the fibroproliferative process is not responsive to pulmonary vasodilators. Another explanation could be worsening left side function with increase pulmonary capillary pressure and congestion associated with interstitial edema. In fact, similar findings are noted in heart failure, in which acute decompensation and increased wedge pressure cause a drop in Dm paralleled by an increase in Vc. Worsening RV function in PAH can lead to LV dysfunction through ventricular interdependence. Our findings showed that Vc increased with worsening RV function but there was no relation between Vc and LV function. In view of the limitations of echocardiography and the absence of repeat right heart catheterization, the contribution of LV dysfunction to the increase of Vc noted over time remains undetermined. Overall, the lack of perceptible changes in standard clinical markers highlights the limitations of available tests, and suggests the possibility that lung diffusing capacity as measured by NO, i.e. the lung Dm, may be a potential marker for disease progression in PAH. A limitation of the study is the small number of patients followed longitudinally and studies with a large cohort of PAH patients over time in correlation with clinical parameters and outcomes are needed to confirm our findings.
Evidence of airway obstruction in PAH is suggested in this study based on the decreased %FEV1 and FEV1/FVC. This is in keeping with published data that identifies peripheral airway obstruction in PAH by lung functions and pathologic findings [22–26]. Inflammation typically surrounds plexiform lesions in PAH  and abundant mast cells have been noted in PAH lungs . Lung biopsies show small airways narrowing with thickened walls infiltrated by lymphocytes, plasma cells and polymorphonuclear leukocytes . Moreover, studies reveal shared mechanistic features of asthma and PAH in experimental models [30, 31]. Thus, although PAH is defined as a pure vascular disease, impaired airflow occurs in patients on PAH therapies, suggesting a potential role for airway-directed therapies in the care of these patients.
There are several limitations to the study. Patients were recruited from our PH clinic and the research testing was done on the day of their scheduled clinical visits. Their primary physician scheduled follow up visits and adjusted PAH therapy. We had no control on the time interval between visits or on treatment. As such though most patients were stable on their PAH therapies, the effect of medications on the findings can not be excluded. Another limitation is the difference in age between the PAH and control groups. However, the novel finding here is the longitudinal changes in the PAH group. The drop in Dm over time has not been described previously. Another limitation is the lack of concurrent hemodynamic data at the time of the DL measurements. Future studies evaluating Dm and Vc in relation to hemodynamic data are essential to better understand the significance of the changes noted here.