Pulmonary microvascular lesions regress in reperfused chronic thromboembolic pulmonary hypertension

J Heart Lung Transplant. 2015 Mar;34(3):457-67. doi: 10.1016/j.healun.2014.07.005. Epub 2014 Jul 16.

Abstract

Background: Pulmonary microvascular disease (PMD) develops in both occluded and non-occluded territories in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and may cause persistent pulmonary hypertension after pulmonary endarterectomy. Endothelin-1 (ET-1) and interleukin-6 (IL-6) are potential PMD severity biomarkers, but it remains unknown whether they are related to occluded or non-occluded territories. We assessed PMD and ET-1/IL-6 gene expression profiles in occluded and non-occluded territories with and without chronic lung reperfusion in an animal CTEPH model.

Methods: Chronic PH was induced in 10 piglets by left pulmonary artery (PA) ligation followed by weekly embolization of right lower lobe arteries with enbucrilate tissue adhesive for 5 weeks. At Week 6, 5 of 10 animals underwent left PA reperfusion. At Week 12, animals with and without reperfusion were compared with sham animals (n = 5). Hemodynamics, lung morphometry and ET-1/IL-6 gene expression profiles were assessed in the left lung (LL, occluded territories) and right upper lobe (RUL, non-occluded territories).

Results: At Week 12, mean PA pressure remained elevated without reperfusion (29.0 ± 2.8 vs 27.0 ± 1.1 mm Hg, p = 0.502), but decreased after reperfusion (30.0 ± 1.5 vs 20.5 ± 1.7 mm Hg, p = 0.013). Distal media thickness in the LL and RUL PAs and systemic vasculature to the LL were significantly lower in the reperfused and sham groups compared with the non-reperfused group. PMD progression was related to ET-1 and IL-6 gene expression in the RUL and to the ET-A/ET-B gene expression ratio in the LL.

Conclusions: PMD regressed in occluded and non-occluded territories after lung reperfusion. Changes in ET-1 and IL-6 gene expression were associated with PMD in non-occluded territories.

Keywords: chronic thromboembolic pulmonary hypertension; endothelin-1; interleukin-6; microvascular disease; pulmonary endarterectomy; pulmonary hypertension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopsy
  • Cytokines / blood
  • Disease Models, Animal
  • Hypertension, Pulmonary / diagnosis*
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / metabolism
  • Lung / blood supply
  • Lung / pathology*
  • Male
  • Microcirculation*
  • Pulmonary Artery / pathology*
  • Pulmonary Artery / physiopathology
  • Pulmonary Circulation*
  • Pulmonary Embolism / complications*
  • Pulmonary Embolism / diagnosis
  • Pulmonary Embolism / physiopathology
  • Reperfusion Injury
  • Severity of Illness Index
  • Swine
  • Vascular Resistance*

Substances

  • Cytokines