Modeling Pulmonary Hypertension: A Pig Model of Postcapillary Pulmonary Hypertension

  • Olympia Bikou
  • Kiyotake Ishikawa
  • Kenneth M. Fish
  • Iratxe Zarragoikoetxea
  • Roger J. Hajjar
  • Jaume Aguero
Part of the Methods in Molecular Biology book series (MIMB, volume 1816)


Pulmonary hypertension (PH) is a pathophysiological condition defined as an increase in mean pulmonary arterial pressure ≥25 mmHg at rest assessed by right heart catheterization.

Based on hemodynamic criteria, precapillary PH is characterized by a mean pulmonary capillary wedge pressure ≤15 mmHg as opposed to the postcapillary PH by >15 mmHg. Postcapillary PH is one of the most common forms of PH, often caused by left ventricular dysfunction and heart failure.

In this chapter, we describe protocols for creating a large animal model of postcapillary PH. It is induced by open chest surgery (lateral thoracotomy) to band the pulmonary veins. The model is characterized by low mortality, relatively easy surgical procedure with well reproducible results, and pulmonary and cardiac remodeling at the structural, functional, and molecular levels. The presence of right ventricular (RV) remodeling is of significant importance since right heart failure is the main cause of death in patients suffering from PH. One of the advantages of the model described in this chapter is that both adaptive and maladaptive forms of RV remodeling can be observed during the progression of the disease. This can help understand the progressive pathophysiology of RV failure in humans. Besides the description of the model, a detailed guidance of the RV functional assessment in pigs for both invasive (heart catheterization) and noninvasive (echocardiography) approaches is provided.

Key words

Pulmonary hypertension Animal model Large animal Postcapillary pulmonary hypertension Right heart failure Right heart echocardiography 



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. O.B. was supported by the Deutsche Herzstiftung.


  1. 1.
    Galie N, Humbert M, Vachiery JL, 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, Aboyans V, Vaz Carneiro A, Achenbach S, Agewall S, Allanore Y, Asteggiano R, Paolo Badano L, Albert Barbera J, Bouvaist H, Bueno H, Byrne RA, Carerj S, Castro G, Erol C, Falk V, Funck-Brentano C, Gorenflo M, Granton J, Iung B, Kiely DG, Kirchhof P, Kjellstrom B, Landmesser U, Lekakis J, Lionis C, Lip GY, Orfanos SE, Park MH, Piepoli MF, Ponikowski P, Revel MP, Rigau D, Rosenkranz S, Voller H, Luis Zamorano J (2016) 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the 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):67–119. Scholar
  2. 2.
    Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S, Fishman A (2004) Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43(12 Suppl S):5S–12S. Scholar
  3. 3.
    Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF (2009) Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol 297(6):L1013–L1032. Scholar
  4. 4.
    Dickinson MG, Bartelds B, Borgdorff MA, Berger RM (2013) The role of disturbed blood flow in the development of pulmonary arterial hypertension: lessons from preclinical animal models. Am J Physiol Lung Cell Mol Physiol 305(1):L1–L14. Scholar
  5. 5.
    Humbert M, Montani D, Evgenov OV, Simonneau G (2013) Definition and classification of pulmonary hypertension. Handb Exp Pharmacol 218:3–29. Scholar
  6. 6.
    Rich S, Rabinovitch M (2008) Diagnosis and treatment of secondary (non-category 1) pulmonary hypertension. Circulation 118(21):2190–2199. Scholar
  7. 7.
    Opitz CF, Hoeper MM, Gibbs JS, Kaemmerer H, Pepke-Zaba J, Coghlan JG, Scelsi L, D'Alto M, Olsson KM, Ulrich S, Scholtz W, Schulz U, Grunig E, Vizza CD, Staehler G, Bruch L, Huscher D, Pittrow D, Rosenkranz S (2016) Pre-capillary, combined, and post-capillary pulmonary hypertension: a pathophysiological continuum. J Am Coll Cardiol 68(4):368–378. Scholar
  8. 8.
    Lau EMT, Giannoulatou E, Celermajer DS, Humbert M (2017) Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol 14(10):603–614. Scholar
  9. 9.
    Gomez-Arroyo J, Sandoval J, Simon MA, Dominguez-Cano E, Voelkel NF, Bogaard HJ (2014) Treatment for pulmonary arterial hypertension-associated right ventricular dysfunction. Ann Am Thorac Soc 11(7):1101–1115. Scholar
  10. 10.
    van Campen JS, de Boer K, van de Veerdonk MC, van der Bruggen CE, Allaart CP, Raijmakers PG, Heymans MW, Marcus JT, Harms HJ, Handoko ML, de Man FS, Vonk Noordegraaf A, Bogaard HJ (2016) Bisoprolol in idiopathic pulmonary arterial hypertension: an explorative study. Eur Respir J 48(3):787–796. Scholar
  11. 11.
    Rosenkranz S, Gibbs JS, Wachter R, De Marco T, Vonk-Noordegraaf A, Vachiery JL (2016) Left ventricular heart failure and pulmonary hypertension. Eur Heart J 37(12):942–954. Scholar
  12. 12.
    Colvin KL, Yeager ME (2014) Animal models of pulmonary hypertension: matching disease mechanisms to etiology of the human disease. J Pulm Respir Med 4(4):198. Scholar
  13. 13.
    Maarman G, Lecour S, Butrous G, Thienemann F, Sliwa K (2013) A comprehensive review: the evolution of animal models in pulmonary hypertension research; are we there yet? Pulm Circ 3(4):739–756. Scholar
  14. 14.
    Pereda D, Garcia-Alvarez A, Sanchez-Quintana D, Nuno M, Fernandez-Friera L, Fernandez-Jimenez R, Garcia-Ruiz JM, Sandoval E, Aguero J, Castella M, Hajjar RJ, Fuster V, Ibanez B (2014) Swine model of chronic postcapillary pulmonary hypertension with right ventricular remodeling: long-term characterization by cardiac catheterization, magnetic resonance, and pathology. J Cardiovasc Transl Res 7(5):494–506. Scholar
  15. 15.
    Aguero J, Ishikawa K, Hadri L, Santos-Gallego C, Fish K, Hammoudi N, Chaanine A, Torquato S, Naim C, Ibanez B, Pereda D, Garcia-Alvarez A, Fuster V, Sengupta PP, Leopold JA, Hajjar RJ (2014) Characterization of right ventricular remodeling and failure in a chronic pulmonary hypertension model. Am J Phys Heart Circ Phys 307(8):H1204–H1215. Scholar
  16. 16.
    Gomez-Arroyo JNI, Yu PB (2016) Animal models of pulmonary hypertension. In: Maron BA, Zamanian RT, Waxman AB (eds) Pulmonary hypertension. Springer, ChamGoogle Scholar
  17. 17.
    Swindle MM (2007) Swine in the laboratory surgery, anesthesia, imaging, and experimental techniques. CRC Press, Boca RatonCrossRefGoogle Scholar
  18. 18.
    Vandecasteele T, Vandevelde K, Doom M, Van Mulken E, Simoens P, Cornillie P (2015) The pulmonary veins of the pig as an anatomical model for the development of a new treatment for atrial fibrillation. Anat Histol Embryol 44(1):1–12. Scholar
  19. 19.
    Bradbury AG, Eddleston M, Clutton RE (2016) Pain management in pigs undergoing experimental surgery; a literature review (2012–4). Br J Anaesth 116(1):37–45. Scholar
  20. 20.
    Ison SH, Clutton RE, Di Giminiani P, Rutherford KM (2016) A review of pain assessment in pigs. Front Vet Sci 3:108. Scholar
  21. 21.
    Lecour S, Botker HE, Condorelli G, Davidson SM, Garcia-Dorado D, Engel FB, Ferdinandy P, Heusch G, Madonna R, Ovize M, Ruiz-Meana M, Schulz R, Sluijter JP, Van Laake LW, Yellon DM, Hausenloy DJ (2014) ESC working group cellular biology of the heart: position paper: improving the preclinical assessment of novel cardioprotective therapies. Cardiovasc Res 104(3):399–411. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Olympia Bikou
    • 1
  • Kiyotake Ishikawa
    • 1
  • Kenneth M. Fish
    • 1
  • Iratxe Zarragoikoetxea
    • 1
    • 2
  • Roger J. Hajjar
    • 1
  • Jaume Aguero
    • 1
    • 2
    • 3
  1. 1.Cardiovascular Research CenterIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Hospital Universitari i Politecnic La FeValenciaSpain
  3. 3.Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)MadridSpain

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