Persistence of complex vascular lesions despite prolonged prostacyclin therapy of pulmonary arterial hypertension

Abstract

Aims: Continuous infusion of prostacyclin analogues improves survival in advanced pulmonary arterial hypertension. In addition to its vasodilatory effects, prostacyclin has the potential to decrease inflammation, thrombosis, and smooth muscle proliferation. The aim of this retrospective study was to determine whether pathological data support the ability of prostanoids to prevent progression of vascular disease.

Methods and results: Twenty-two autopsied patients with World Health Organization category 1 pulmonary arterial hypertension (primarily idiopathic and connective tissue disease-associated) were divided into those who received long-term prostacyclin (n = 12, PG-long, mean treatment 3.9 years) and those who received 0-1 month of prostacyclin (n = 10, PG-short). Surprisingly, PG-long patients had larger plexiform lesions (P < 0.05), with no decrease in medial and intimal thicknesses as compared with PG-short patients. Plexiform lesion size and density increased with increasing treatment time. Also, PG-long patients had fewer platelet thrombi and more frequent acute diffuse alveolar haemorrhage. Quantification of macrophages and T cells revealed no differences in inflammatory infiltrates.

Conclusion: Although long-term prostacyclin therapy may have an antithrombotic effect in addition to its vasodilatory actions, it was not associated with the prevention of advanced vascular lesions. The mechanism by which prostacyclin analogues improve survival in pulmonary arterial hypertension remains uncertain.

Keywords: histopathology; plexiform lesions; prostaglandins; vascular remodelling.

Figure 1

Arterial remodeling. A, Elastic stained muscular artery of a prostacyclin-treated patient with intimal fibrosis showing measurements of medial thickness (MT), intimal thickness (IT), and external diameter (ED). B, Quantification of medial and intimal thicknesses in PG-short and PG-long patients showed no significant difference in medial or intimal thicknesses. With increasing prostacyclin treatment time, there was no decrease in medial thickness (C) and there was a non-significant trend towards increased intimal thickness (D).

Figure 2

Patients treated with prostacyclin have large, proximal vascular lesions. A,B, Small, distal plexiform lesion in an untreated patient. The lesion is alongside an alveolar duct (arrow). C,D, Large, prealveolar plexiform lesion in a prostacyclin-treated patient. The lesion is at a small artery branching off a larger artery accompanying a bronchiole (arrow).

Figure 3

Effect of prostacyclin treatment on plexiform lesions. A, Prostacyclin-treated patients had significantly (*P = 0.040) larger plexiform lesions. B, Plexiform lesion density in prostacyclin-treated patients was not significantly different from that in untreated patients. C, Plexiform lesions in prostacyclin-treated patients were not significantly more likely to be associated with more proximal vessels. D, Plexiform lesions were significantly larger with increasing treatment time (P = 0.031). E, Plexiform lesion density significantly increased with increasing treatment time (P = 0.006). F, Plexiform lesion association with bronchiolar arteries showed a non-significant increase with treatment time.

Figure 4

Inflammation in pulmonary arterial hypertension, ×100. A,B, CD3-positive T cells (A) and CD68-positive macrophages (B) in an untreated PAH patient. C,D, CD3-positive T cells (C) and CD68-positive macrophages (D) in a prostacyclin-treated patient.

Figure 5

Quantification of arterial inflammation. A, Outline of plexiform lesion in the Automated Cellular Imaging System (ACIS) to select areas for quantification. B, Quantification of inflammation showed no significant difference between PG-short and PG-long patients.

Figure 6

Effect of prostacyclin on platelet aggregates. A, CD61 immunohistochemistry highlights platelet aggregates within a plexiform lesion of an untreated patient. B, CD61 immunohistochemistry shows no platelet aggregates in a plexiform lesion from a prostacyclin-treated patient. C, Quantification of platelet aggregates shows significantly fewer aggregates in plexiform lesions and vessels, but no significant increase in capillary aggregates in PG-long patients as compared with PG-short patients.