Chronic Pulmonary Artery Embolization Models in Large Animals
A wide range of approaches have been described to develop animal models of pulmonary vascular disease (PVD). Clinical heterogeneity in patients with pulmonary hypertension (PH) has prompted development of different techniques to create PH models in several animal species with the objective to recapitulate specific PH/PVD phenotypes. Chronic thromboembolic PH (CTEPH) is a clinically important phenotype of PH with a documented prevalence of 0.4–9.1% in patients with history of pulmonary embolism. A well-established large animal model of CTEPH is thus necessary for studying this disease in preclinical research. Different experimental protocols with inconsistent outcomes have been reported in the literature.
We have focused on characterizing PH large animal models in a common framework; pulmonary hemodynamics, right ventricular (RV) function, and histological characterization of PVD. This research framework allows optimal evaluation of novel diagnostic tools, as well as new therapeutic strategies. The purpose of this protocol is to describe approaches to create experimental CTEPH models using recurrent pulmonary embolizations of dextran microspheres in swine. The key features of this experimental modeling approach are (1) nonsurgical, fully percutaneous techniques, (2) a minimum of four embolization procedures, with 1–2 month time period, (3) mild to moderate PH hemodynamics (mean PA pressure increase ~20–60%), (4) severe pulmonary vascular remodeling, (5) mild RV remodeling, and (6) a high reproducibility and low mortality (<10%).
Key wordsPulmonary hypertension Pulmonary embolization Large animal disease models Vascular remodeling Pulmonary vascular disease
This work is supported by NIH R01 HL139963 (K.I.), HL117505, HL 119046, HL129814, 128072, HL131404, HL135093, a P50 HL112324 (R.J.H.), AHA-SDG 17SDG33410873 (K.I.), and two Transatlantic Fondation Leducq grants. We would like to acknowledge the Gene Therapy Resource Program (GTRP) of the National Heart, Lung, and Blood Institute, National Institutes of Health. J.A. was supported by the Fundacion Alfonso Martin-Escudero. N.H. was supported by the French Federation of Cardiology.
- 1.Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M (2016) 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertensionThe joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37(1):67–119CrossRefGoogle Scholar
- 3.Pepke-Zaba J, Delcroix M, Lang I, Mayer E, Jansa P, Ambroz D, Treacy C, D'Armini AM, Morsolini M, Snijder R, Bresser P, Torbicki A, Kristensen B, Lewczuk J, Simkova I, Barbera JA, de Perrot M, Hoeper MM, Gaine S, Speich R, Gomez-Sanchez MA, Kovacs G, Hamid AM, Jais X, Simonneau G (2011) Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation 124(18):1973–1981. https://doi.org/10.1161/CIRCULATIONAHA.110.015008CrossRefPubMedGoogle Scholar
- 6.Aguero J, Ishikawa K, Fish KM, Hammoudi N, Hadri L, Garcia-Alvarez A, Ibanez B, Fuster V, Hajjar RJ, Leopold JA (2015) Combination proximal pulmonary artery coiling and distal embolization induces chronic elevations in pulmonary artery pressure in swine. PLoS One 10(4):e0124526. https://doi.org/10.1371/journal.pone.0124526CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Garcia-Alvarez A, Fernandez-Friera L, Garcia-Ruiz JM, Nuno-Ayala M, Pereda D, Fernandez-Jimenez R, Guzman G, Sanchez-Quintana D, Alberich-Bayarri A, Pastor-Escuredo D, Sanz-Rosa D, Garcia-Prieto J, Gonzalez-Mirelis JG, Pizarro G, Jimenez-Borreguero LJ, Fuster V, Sanz J, Ibanez B (2013) Noninvasive monitoring of serial changes in pulmonary vascular resistance and acute vasodilator testing using cardiac magnetic resonance. J Am Coll Cardiol 62(17):1621–1631. https://doi.org/10.1016/j.jacc.2013.07.037CrossRefPubMedGoogle Scholar