Endothelin-1 overexpression in pulmonary endarterectomy specimens of CTEPH patients is associated with pulmonary hypertension development

Abstract

Background: Endothelin-1 (ET-1) is associated with pulmonary hypertension (PH) in pulmonary arterial hypertension patients. The role of ET-1 in chronic thromboembolic pulmonary hypertension (CTEPH) is not well defined. Therefore, we aimed to explore the contributions of organized thromboembolic material as a source of ET-1.

Methods: 40 CTEPH patients with mPAP ≥ 50 mmHg (higher mPAP group) and 35 patients with mPAP ≤25 mmHg (lower mPAP group) who underwent pulmonary endarterectomy (PEA) were studied. Fresh frozen PEA samples were used to perform qRT-PCR, while paraffin samples were analyzed by immunohistochemistry staining for ET-1 quantification. Preoperative CT pulmonary angiograms were reviewed to assess the total number of vessel occlusions in the lungs of the higher mPAP and lower mPAP groups.

Results: The higher mPAP group showed significantly higher ET-1 protein (p < 0.0001) and mRNA (p=0.0003) expression in PEA specimens than the lower mPAP group. We found a positive ET-1 protein and mRNA correlation with transpulmonary resistance. CT scans showed no difference in overall obstruction of the pulmonary vascular tree between lower and higher mPAP groups (p=0.0929), but a significantly higher number of segmental (p=0.0362) and subsegmental vessels (p=0.0029) were blocked in the higher mPAP group. Overall, female patients had higher expression of ET-1 in the higher mPAP group as compared to the lower mPAP group and also had a significantly higher number of subsegmental vessels obstructed (p=0.0084).

Conclusions: ET-1 release from thromboembolic material of CTEPH patients could be an important mechanism leading to PH. Hence, ET-1 receptor antagonists should continue to be investigated as a potential therapeutic agent in CTEPH patients.

Keywords: CTEPH; Endothelin-1; Pulmonary Hypertension.