04 February 2019 by Rozenn Quarck

Repeated embolization with blood clots containing an inhibitor of angiogenesis induces chronic thromboembolic pulmonary hypertension in rabbits

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe disease characterized by unresolved and organized thrombi obstructing the pulmonary arterial bed, resulting in PH and right ventricular (RV) failure. We previously observed that repeated embolization with blot clots combined with fibrinolysis inhibition resulted in histological signs of CTEPH in rabbits. A role of neovascularization in the resolution of venous thrombi has been suggested and angiogenic factors such as vascular endothelial growth factor (VEGF) were found in resolving thrombi.

We hypothesized that inhibition of angiogenesis may prevent clot resolution and promote CTEPH progression. We aimed to investigate whether repeated embolization with blood clots containing an inhibitor of angiogenesis may induce CTEPH in rabbits.

Adult male New Zealand rabbits were weekly embolized for 7 weeks with blood clots alone, containing tranexamic acid (TXA), a fibrinolysis inhibitor or Sugen™, an inhibitor of VEGF receptor, or together with an intravenous injection of TXA. A sham-operated group received saline. RV systolic pressure (RVSP) was monitored by telemetry. Right heart catheterization was performed 8 weeks after the last embolization. RV function was assessed by transthoracic echocardiography at baseline, after the last embolization and before sacrifice. RV hypertrophy and lung vessel morphometry were analyzed.

Repeated embolization with clots containing Sugen™ resulted in a 2.4-fold increase in mean pulmonary arterial pressure, a 4.2-fold increase in pulmonary vascular resistance index without any change in cardiac output, a 1.5-fold increase in Fulton index and a 37 % increase in RV diameter compared to baseline. It also induced fibro-thrombotic lesions in large proximal pulmonary arteries with a 2.8 fold increase in neointima thickness and remodeling of distal pulmonary arteries.

Local inhibition of angiogenesis combined with repeated blood clot embolization promoted CTEPH progression in rabbits. Obstruction of large proximal pulmonary arteries by fibro-thrombotic lesions highlights the similarity with the human pathology of CTEPH.

About the author


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Rozenn Quarck

Scientist

KU Leuven/University Hospitals Leuven

Belgium

Key Contributors

R. Quarck 1, A. Wagenaar 2, B. Tielemans 2, P. Mendes-Ferreira 2, F. Perros 3, P. Dorfmuller 3, C. Belge 1, M. Delcroix 1 : 1.Respiratory Division, University Hospitals Leuven & Department of Chronic Diseases, Metabolism & Aging, KU Leuven, Leuven, Belgium; 2.Respiratory Division, Department of Chronic Diseases, Metabolism & Aging, KU Leuven - Leuven (Belgium), 3.UMR-S 999, INSERM and Université Paris–Sud, Laboratoire d’Excellence (LabEx) en Recherche sur le Médicament et l’Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue - Le Plessis-Robinson (France)


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