Pulmonary Circulation 2017; 7(1) 1Š11

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



Abraham Rothman, MD1,2, Robert G Wiencek, MD3, Stephanie Davidson, MD4, William N Evans, MD1,2, Humberto Restrepo, MD, MPH1,2, Valeri Sarukhanov1, David Mann5


1ChildrenÕs 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 



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



Pulmonary hypertension (PH) results in significant morbidity and mortality. Chronic PH animal models may advance the study of PHÕs 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 2Š3 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 modelÕs characteristics need to match the investigational goals.


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