Pulmonary Circulation 2017; 7(1) 1–11

DOI: 10.1086/690099

Date received: 22 July 2016; accepted: 7 November 2016

! 2017 by Pulmonary Vascular Research Institute.

Challenges in the Development of Chronic Pulmonary Hypertension Models in Large Animals

Author

Abraham Rothman, MD^1,2, Robert G Wiencek, MD³, Stephanie Davidson, MD⁴, William N Evans, MD^1,2, Humberto Restrepo, MD, MPH^1,2, Valeri Sarukhanov¹, David Mann⁵

¹Children’s Heart Center Nevada, Las Vegas, NV, USA; ²University of Nevada, School of Medicine, Department of Pediatrics, Las Vegas, NV, USA; ³Stanford University, Department of Cardiothoracic Surgery, Cardiothoracic Dignity Healthcare, Las Vegas, NV, USA; ⁴Anesthesiologist Consultants Inc., Las Vegas, NV, USA; ⁵Vascular BioSciences, Goleta, CA, USA

Source

Children’s Heart Center Nevada, 3006 S Maryland Pkwy, Ste 690, Las Vegas, Nevada 89109, USA. Email: arothman@childrensheartcenter.com.

Abstract

Pulmonary hypertension (PH) results in significant morbidity and mortality. Chronic PH animal models may advance the study of PH’s mechanisms, evolution, and therapy. In this report, we describe the challenges and successes in developing three models of chronic PH in large animals: two models (one canine and one swine) utilized repeated infusions of ceramic microspheres into the pulmonary vascular bed, and the third model employed a surgical aorto-pulmonary shunt. In the canine model, seven dogs underwent microsphere infusions that resulted in progressive elevation of pulmonary arterial pressure over a few months. In this model, pulmonary endoarterial tissue was obtained for histology. In the aorto-pulmonary shunt swine model, 17 pigs developed systemic level pulmonary pressures after 2–3 months. In this model, pulmonary endoarterial tissue was sequentially obtained to assess for changes in gene and microRNA expression. In the swine microsphere infusion model, three pigs developed only a modest chronic increase in pulmonary arterial pressure, despite repeated infusions of microspheres (up to 40 in one animal). The main purpose of this model was for vasodilator testing, which was performed successfully immediately after acute microsphere infusions. Chronic PH in large animal models can be successfully created; however, a model’s characteristics need to match the investigational goals.

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