A swine model of severe chronic thromboembolic pulmonary hypertension induced by repeated pulmonary artery long suture injection.

INTRODUCTION: Large animal models are key to translational research. Current models of chronic thromboembolic pulmonary hypertension (CTEPH) are rather complex, impractical and most fail to achieve a severe PH and right ventricular (RV) dysfunction phenotype. Our aim was to develop a plain large animal model of severe CTEPH with RV dysfunction. METHODS: In 3 consecutive weeks, 2-month-old male pigs (∼25 kg) randomly underwent either left and right pulmonary artery (PA) injection of 15-30 15†cm #0 silk sutures (CTEPH, n = 9) or sham procedure (Sham, n = 6). Embolization was interrupted based on mean PA pressure (mPAP) elevation, cardiac output (CO) or systemic blood pressure decline, or complete obstruction on angiography. After 4 weeks of follow-up, we assessed echocardiography, biventricular pressure-volume (PV) hemodynamics, RV skinned cardiomyocyte, lung and RV histology, and RV gene expression and protein levels. RESULTS: At terminal evaluation, mPAP was consistently higher in CTEPH compared with Sham (51 ± 3 vs. 20 ± 1†mmHg, respectively; P < 0.001) with reduced CO (4.2 ± 0.2 vs. 6.6 ± 0.9†L.min(-1); P = 0.042). On angiography, most of the PA territory was obstructed, with cephalad redirection of flow. RV hypertrophy was clear on morphology, echocardiography and histology. CTEPH showed decreased RV ejection fraction (35 ± 2 vs. 51 ± 3%; P < 0.001), delayed relaxation, and end-diastolic stiffening but preserved ventricle-vascular coupling. Although fibrosis was not observed on histology and collagen chain expression was not upregulated in RV myocardium, skinned RV cardiomyocytes from CTEPH did show passive stiffening as well as higher active tension development. CTEPH RV showed altered gene expression of myosin heavy chains and B-type natriuretic peptide as well as decreased sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA2a) expression. Both SERCA2a and phosphorylated phospholamban protein levels were decreased as well. Medial hypertrophy was observed in distal arteries from the unobstructed right cranial lobe of CTEPH denoting flow-induced vasculopathy. DISCUSSION: We developed a new and straightforward swine model of severe CTEPH with RV dysfunction by repeated injection of long sutures into the PA without the need for additional hits which may be valuable for preclinical research.