Long-term effects of epoprostenol on the pulmonary vasculature in idiopathic pulmonary arterial hypertension

Abstract

The current treatment of pulmonary arterial hypertension (PAH) uses vasodilator drugs. Although they improve symptoms associated with PAH, their chronic effects on the pulmonary vasculature and the right ventricle (RV) in humans remain unknown. We report the autopsy findings from a patient with idiopathic PAH treated with epoprostenol successfully for 18 years. The patient died of colon cancer. The pulmonary vasculature surprisingly showed extensive changes of a proliferative vasculopathy. Immunohistochemical studies confirmed ongoing cellular proliferation. Studies of the RV demonstrated concentric hypertrophy with seemingly preserved contractility. The myocardium shifted to glycolytic metabolism. Although the long-term use of epoprostenol contributed to the patient's increased survival, it did not prevent progression of the underlying vascular disease. Remarkably, the RV was able to sustain a normal cardiac output in the face of advanced vascular pathology. The mechanisms by which the RV adapts to chronic PAH need further study.

Figure 1.

A, A small branch of pulmonary artery with severe medial hypertrophy and mild intimal fibrosis causing severe luminal obstruction (hematoxylin-eosin stain, original magnification ×20). These findings were typical of most of the arterioles in this patient. B, A characteristic plexiform lesion surrounded by dilated, thin-walled vessels (hematoxylin-eosin stain, original magnification ×4). C, Immunofluorescent staining for proliferating cell nuclear antigen (PNCA) (red) indicative of ongoing vascular proliferation. The bright staining (green) is smooth muscle actin. The staining of the pulmonary vasculature from another patient who died without pulmonary vascular disease is shown for comparison as a normal control. Staining for PNCA is absent in the normal control. PAH=pulmonary arterial hypertension.

Figure 2.

A, The heart of our patient with PAH (in cross section) showing severe concentric RV hypertrophy is presented adjacent to a patient with idiopathic PAH (IPAH) who died of severe RV failure for comparison. There is a striking difference in the geometry of the RV in these patients. B, Representative immunofluorescent staining of the RV and left ventricle (LV) myocardium for SERCA2A in our patient is shown alongside a sample from the patient who died of severe RV failure and a normal control. The mean fluorescent intensity, normalized to dystrophin, also is displayed (right). The intensity in the RV and LV appear to be similar between the long-term surviving patient and the normal control but diminished in the RV when compared with the LV in the patient who died of RV failure. C, PDK4 (green) and Glut1 expression are shown in our patient with PAH alongside the patient who died of severe RV failure and the normal control. There is increased expression of PDK4 and Glut1 in our patient’s RV compared with her LV and compared with the normal control. However, there appears to be less upregulation when compared with the patient who died of severe RV failure. In all RV micrographs, the bar indicates 100 μm. DAPI=4′,6-diamidino-2-phenylindole; Glut1=glucose transporter; PDK4=pyruvate dehydrogenase kinase-4; RV=right ventricle; SERCA2A=sarcoplasmic reticulum calcium adenosine triphosphatase. See Figure 1 legend for expansion of other abbreviation.