Background: Pulmonary arterial hypertension (PAH) may be idiopathic (IPAH), or related to a variety of disorders, including connective tissue disease (CTD). All types of PAH cause structural remodeling and obstruction of the precapillary pulmonary vascular bed, and loss of perfused functional pulmonary capillary surface area (FCSA). Reduction in the levels of single-breath carbon monoxide diffusing capacity (DLCO) is one of the early signs of development of PAH in patients with CTD. Normal DLCO depends on an absence of alveolar thickening and interstitial disease, as well as an adequate number of perfused capillaries in close proximity to alveoli to permit efficient gas exchange.
Objectives: It has been proposed that the fall in DLCO in early PAH from CTD is due to loss of capillary perfusion, but a relationship has never been demonstrated. We proposed that such a relationship would exist.
Methods: To test this hypothesis, we measured the first pass metabolism of a specific substrate (³H-BPAP) for the pulmonary capillary angiotensin converting ectoenzyme (ACE), in humans with PAH (25 idiopathic and 19 CTD: 3 diffuse scleroderma, 9 limited scleroderma, 1 SLE, 1 MCTD, 1 polymyositis, 3 RA, 1 overlap). 23 controls without PAH were also studied. The enzymatic cleavage of BPAP occurs with first order kinetics, and we calculated A_max/K_m, an index of FCSA, normalized to body surface area (BSA), and looked for a correlation with DLCO (% predicted).
Results: A_max/K_m/BSA for both IPAH (mean 1339+153 SEM) and CTD (953+110) was significantly reduced compared to controls (3119+324). For IPAH, the correlation between A_max/K_m/BSA was poor (r=0.34), whereas it was stronger for PAH-CTD (r=0.53, p <0.05).

Conclusion: This is the first demonstration that the reduction in DLCO in PAH-CTD is at least in part related to loss of functional capillary surface area, and is proportional to its severity.