To the Editors:
We read with great interest the recent article by Overbeek et al. 1 on the histological differences in pulmonary vessels from patients with pulmonary arterial hypertension (PAH) related to systemic sclerosis (SSc) versus idiopathic PAH (IPAH). The study demonstrates that pulmonary pathological features in patients suffering from limited cutaneous SSc (lcSSc) differ from the ones seen in IPAH, in relation to the occurrence of small vessel intimal fibrosis, the presence of pulmonary veno-occlusive disease-like lesions, and the absence of plexiform lesions in the former group. Overbeek et al. 1 correctly suggest that their findings point to the presence of a distinct vasculopathy in the SSc cohort that may contribute to the lower transfer factor of the lung for carbon monoxide (TL,CO) and, more importantly, to the worse prognosis in PAH-SSc versus IPAH. The authors further propose that different pathogenetic mechanisms should underlie PAH development in the two groups, and that pulmonary endothelial function should be a determinant of such dissimilar mechanisms 1.
In support of the this hypothesis, we have recently provided evidence that different degrees of pulmonary endothelial dysfunction may be present in patients suffering from IPAH and PAH related to connective tissue disease (PAH-CTD) 2. Using first-pass lung metabolic studies at the bedside, by means of indicator dilution-type techniques, we have been studying human pulmonary endothelial function by estimating pulmonary capillary endothelium-bound enzymatic activity in vivo 3. This technique allows direct and quantifiable measurements of pulmonary endothelial metabolic function, and may distinguish between functional alterations at the capillary endothelial cell level and loss of functional capillary surface area (i.e. perfused and metabolically active lung microvascular bed) 3.
By applying such techniques we have, in the past, provided in vivo evidence that pulmonary endothelial dysfunction is a feature of early systemic sclerosis, being already present prior to the development of PAH and overt interstitial lung disease 4. Patients suffering from both lcSSc and diffused cutaneous SSc (dcSSc) demonstrated functional alterations at the capillary endothelial cell level, whereas the functional capillary surface area was reduced only in dcSSc 4. More recently, we have extended these studies to investigate pulmonary endothelial metabolic functional patterns in subjects with IPAH and PAH-CTD, prior to receiving PAH-related treatments 2. Approximately two-thirds of the PAH-CTD patients suffered from SSc. Indices reflecting “true” pulmonary endothelial dysfunction (i.e. functional alteration at the capillary endothelial cell level) were only present in the CTD group, supporting the intriguing hypothesis that PAH-CTD and IPAH posses different pulmonary endothelial phenotypes, and thus different metabolic functions as implied by Overbeek et al. 1. In contrast, both groups exhibited similar functional capillary surface area reductions, mainly reflecting the PAH-related small vessel loss and remodelling. Furthermore, our study provided the first functional evidence that the reduced TL,CO values in PAH-CTD are related in a linear fashion to the degree of functional capillary surface area loss 2. It should be noted that similar studies performed in patients suffering from chronic thromboembolic pulmonary hypertension revealed a different pattern, in that pulmonary endothelial metabolism was maintained, although functional capillary surface area loss was present 5.
Based on the evidence above, we feel that the study by Overbeek et al. 1 may provide a partial explanation for our findings, and the endothelial dysfunction we described may contribute to the diverse histological abnormalities that Overbeek et al. 1 have presented. Techniques that allow direct quantification of pulmonary endothelial function at the bedside might, in the future, identify varied pulmonary endothelial phenotypes in PAH patients, and assist the clinician in choosing the right treatment and monitoring its effects.
Statement of interest
None declared.
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