Minimally Invasive Porcine Model for Chronic Thromboembolic Pulmonary Hypertension.

Abstract

To elucidate the complex pathophysiology of chronic thromboembolic pulmonary hypertension (CTEPH), a disease associated with bilateral fibrotic obstructions of the pulmonary arteries (PA) and microvascular changes, research relies on animal models, which often depend on invasive techniques, including open surgery. As animal welfare is a major priority for the future of experimental research, and in accordance with the principles of the 3Rs (Replacement, Reduction, and Refinement), this project aimed to develop a fully minimally invasive porcine CTEPH model. In five female large white pigs (50 kg, 3-4 months), an intravascular plug was inserted into the left PA. The right lower lobe artery was embolized weekly for 5 weeks with non-resolving n-butyl-2-cyanoacrylate-glue. Magnetic resonance imaging (MRI) was performed at each intervention. At week 6, plasma molecular and macro- and microscopic analyses were performed. Implantation of the intravascular plug was successful in all animals, without any residual perfusion seen in MRI angiography. Significant increases in mean pulmonary artery pressure (mPAP) (p = 0.005) and mean total pulmonary resistance (TPR) (p = 0.043) were observed. Right ventricle dimensions were significantly increased in all animals. Macroscopically, the left lung developed hypertrophy of bronchial arteries and the right upper lobe overperfusion. Histologically, microvascular wall thickness was increased in both the over-perfused and ischemic territories. Plasma molecular analysis revealed elevated circulating endothelin-1 (p < 0.0001) and reduced nitric oxide metabolites (p = 0.0007). In conclusion, this study establishes a fully minimally invasive refinement of a previously described porcine CTEPH model, including relevant hemodynamic, morphologic, molecular and imaging features of CTEPH while increasing welfare for experimental animals.