Pulmonary arterial hypertension (PAH), classified as Group 1 pulmonary hypertension according to ESC/ERS guidelines (1), is a progressive pulmonary vascular disease caused by a variety of etiologies, including idiopathic pulmonary arterial hypertension (IPAH), heritable PAH (HPAH), congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH), and connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) (1). PAH patients exhibit exertional dyspnea and reduced exercise capacity attributed to right heart dysfunction resulting from increased pulmonary vascular pressure and resistance. However, even after right heart function is improved with optimal PAH-specific treatment, exertional dyspnea remains prevalent among PAH patients, potentially arising from a discrepancy between the neural drive to breathe and the respiratory system’s capacity to respond adequately (2, 3). Mechanical constraints induced by dynamic hyperinflation and excessive ventilatory demand partially elucidate the etiology of exertional dyspnea in patients with PAH who do not exhibit spirometric obstruction (4).

Several studies have aimed to elucidate pulmonary function in patients with pulmonary hypertension (PH) and its association with disease severity and prognosis; however, the conclusions remain inconsistent. Patients with different etiologies exhibit variations in pulmonary function test results. Escribano et al. observed that PAH patients categorized within Venice Groups 1 and 4 demonstrated normal forced vital capacity (FVC), forced expiratory volume in 1 s (FEV₁), and total lung capacity (TLC) but decreased carbon monoxide transfer factor (TLCO). Furthermore, no correlation was found between pulmonary function and hemodynamics (5). Patients with idiopathic pulmonary arterial hypertension (IPAH) demonstrated not only impaired restrictive lung ventilation, characterized by reductions in FVC and FEV₁, but also exhibited impaired diffusion function, evidenced by low diffusion capacity of the lung for carbon monoxide (DLCO), which was positively correlated with exercise capacity (6, 7). Patients with CHD-PAH exhibited both restrictive and obstructive ventilatory impairment, and FVC demonstrated a correlation with 6MWD (8, 9). Patients with CTD-PAH demonstrated only mild restrictive abnormality, and those with TLC > 86.11% exhibited a tendency toward improved response to initial combination therapy in the AMBITION study. Furthermore, PAH associated with scleroderma presented higher mortality rates in correlation with decreased DLCO (10, 11).

As recommended by the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) joint guidelines on pulmonary hypertension (PH), the primary treatment goal of PAH is to achieve and maintain a low-risk status, defined as an expected 1-year mortality of less than 5% (12). In the present study, we established a prospective PAH cohort with diverse etiologies, including IPAH, CHD-PAH, and CTD-PAH. Our objectives are to (1) characterize the pulmonary function profiles of PAH patients and (2) further investigate the association between pulmonary function and risk stratification, both at baseline and at follow-up after 12 months of combined PAH-targeted therapy.

PAH typically exhibits normal or mild restrictive, obstructive, or combined pulmonary function abnormalities (18–20). In the present study, we observed that pulmonary function impairment was associated with different PAH etiologies. CHD-PAH patients demonstrated more severe obstructive ventilation impairment, while CTD-PAH patients exhibited more severe diffusion function impairment, consistent with previous findings (9).

Diffusion capacity of the lung (DL) represents the ability of the lungs to transfer gas from the alveolar space to the red blood cells in pulmonary vessels. Patients with IPAH who are over 50 years of age, male, have a history of smoking, and present with concomitant coronary disease are more likely to exhibit impaired diffusing capacity for carbon monoxide (DLCO) (7). These patients demonstrate reduced exercise performance despite a comparable hemodynamic profile. Farha et al. observed that lung diffusing capacity for nitric oxide (DLNO), but not carbon monoxide (DLCO), decreased in patients with pulmonary arterial hypertension (PAH) over time, indicating a deterioration in the efficiency of the alveolar-capillary unit in PAH (21). Despite exhibiting poorer baseline oxygenation, patients with IPAH and severely reduced DLCO (<43%) demonstrated a comparable response to PAH-targeted therapy as those with moderately reduced or preserved DLCO (22). In the current investigation, we demonstrated impaired DLCO in patients with PAH. Nevertheless, although the DLCO % pred exhibited a negative correlation with PVR, no association was observed with either baseline or follow-up risk status. The differences between our cohort and those previously reported include a relatively younger age, fewer smokers, and fewer coronary comorbidities, which may contribute to the negative DLCO % pred result. Furthermore, the inclusion of PAH patients associated with diverse etiologies may also influence the PFT analysis. The observation that 11% of healthy controls exhibited DLCO% pred values <80%. Several factors may contribute to this finding. First, the inherent technical variability of DLCO measurements, characterized by a higher coefficient of variation (10–15%) compared to spirometry (15), could partially account for these results. Second, undiagnosed comorbidities, such as subclinical emphysema in individuals with smoking exposure (mean pack-year: 1.1 ± 3.8), may have influenced diffusion capacity. Finally, ethnic-specific considerations are relevant; established prediction equations, primarily derived from Caucasian populations, may systematically underestimate DLCO in Asian cohorts, as evidenced by studies in Korean populations (23).

We also evaluated IOS parameters in PAH patients. IOS measures lung resistance at different frequencies to distinguish central and peripheral airway obstruction through regional inhomogeneity. To further differentiate obstruction due to the central airway or the peripheral airway, we conducted IOS analysis. The X5, R5, R5–R20, and R20 represent elastic and interstitial properties, total airway resistance, peripheral airway resistance, and proximal airway resistance, respectively (24). PAH affected lung elasticity, as evidenced by decreased X5. Our integrated analysis of spirometry and oscillometry revealed a distinct pattern of predominantly peripheral, rather than proximal, airway obstruction in CHD-PAH patients. This is evidenced by characteristic reductions in mid-expiratory flows (MEF₇₅, MEF₅₀, MEF₂₅% pred) on spirometry, alongside a significant elevation in R5–R20 (a direct measure of peripheral airway resistance). These convergent data suggest that peripheral, but not proximal, airway obstruction was more prevalent in CHD-PAH patients compared to CTD-PAH and IPAH patients. Although a component of physical lung restriction by enlarged cardiac structures is theoretically possible, the preserved TLC% pred in our CHD-PAH patients argues against it being a primary mechanism. The observed reduction in FVC is more likely a consequence of gas trapping secondary to predominant small airway obstruction.

Abnormal formation or enlargement of vessels can compress the airways and result in small airway obstructions. A close relationship exists between blood vessels and airways throughout lung development (25). Infants with congenital heart disease exhibit an increase in airway smooth muscle and enhanced reactivity (26). The comprehensive remodeling of pulmonary artery hemodynamics in CHD-PAH patients results in more pronounced peripheral airway remodeling.

This study further confirmed that PAH patients had peripheral airway obstruction. A 47-year follow-up of 10,635 patients after congenital heart surgery demonstrated obstructive pulmonary disease as the most common non-cardiovascular morbidity (9%) (27). The possible mechanism includes loss of lung elastic recoil, intrinsic airway narrowing or obliteration, airway inflammation, vasoactive mediators, and mechanical oppression of dilated vessels (8, 13).

In recent times, PAH treatment decisions should be stratified according to disease severity, as assessed through risk stratification. The primary objective is to achieve and maintain a low-risk status, as recommended by clinical guidelines (12). In the present study, we demonstrated that decreased FVC, representing pulmonary ventilation function impairment, resulted in poor risk status improvement after combined target therapy treatment. Two potential explanations are proposed. First, we utilized a four-strata risk-assessment approach, which exhibits increased sensitivity to risk changes from baseline to follow-up (28). This risk assessment tool comprises WHO FC, 6MWD, and BNP/NT-proBNP, with the first two indices reflecting exercise capacity, which is closely associated with ventilation function. Additionally, emerging evidence suggests that lung function is negatively correlated with elevated systemic or paracrine proinflammatory cytokines (29, 30). A close relationship exists between blood vessels and the airways. The pulmonary arteries run alongside and branch from the airways, progressively decreasing in diameter. Perivascular inflammation is a prominent feature in the pathogenesis of PH, and blood cytokine profiles have demonstrated the ability to distinguish PAH immune phenotypes with differing clinical risks independently (31, 32). Consequently, ventilation impairment may deteriorate with the progression of PAH, as demonstrated by Oostveen et al., who observed that FVC decreased by 190 mL/year in PAH patients (17).

There are two major limitations to the study. First, only baseline PFTs, but not PFT changes over time, were included in prognosis analysis. Second, although we did find a relationship between PFT impairment and risk status changes, current results are insufficient for us to conclude whether it is an accompanying phenomenon secondary to PAH progression or a cause of PAH deterioration. A pilot study showed that IPAH patients had significantly increased FEV₁ and CO with decreased PVR after inhaled salbutamol, a ß2-agonist (33). It is unknown whether patients can benefit from long-term regular bronchodilator therapy. A further randomized study is necessary to go deeply into the use of bronchodilators in PAH patients with ventilation impairment.

PAH patients had both ventilation and diffusion capacity impairment. The CHD-PAH patients showed apparent peripheral airway obstruction. FVC and FEV₁ are positively related to 6MWD. PAH patients with FVC% pred <82% showed worse response to PAH-targeted therapy.