Challenges in the development of chronic pulmonary hypertension models in large animals

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.

A Large Animal Model of Right Ventricular Failure due to Chronic Thromboembolic Pulmonary Hypertension: A Focus on Function

“…Many attempts have been made since the 1980's to develop a reliable model of CTEPH in large-animals including pigs, sheep, dogs, cows, and non-human primates with little success. Common techniques typically include some combination of venous thrombosis, surgical ligations or shunts, balloon occlusions, embolic occlusions with microspheres or tissue adhesive, and thrombolytic or VEGF inhibitors (17–23). However, most studies fail to either measure RV function or the model fails to replicate RV failure.…”

Pharmacokinetics of single dose sildenafil orally administered in canine models of chronic embolic pulmonary hypertension

“…After each procedure, the sheath and catheter were removed from the jugular vein. As partial recovery of PAP between each injection day was consistently observed as described previously, this treatment was repeated approximately once a week until sPAP and mPAP prior to microsphere injection exceeded 30 and 20 mmHg, respectively [24]. Then, at least one month was allotted to confirm that sPAP and mPAP exceeded 30 and 20 mmHg, respectively, without further injection.…”

“…The dogs were cathethetised with propofol (6 mg/kg, IV) and intubated, which was maintained using a continuous-rate infusion of propofol (0.1-0. CEPH was induced according to a modified version of a previously described method [18,24]. Briefly, 300-µm microspheres (GE Healthcare, Chicago, IL, USA) were 8 injected into the pulmonary artery through the 4-Fr catheter monitoring PAP.…”

Relationship between right heart echocardiographic parameters and invasive pulmonary artery pressures in canine models of chronic embolic pulmonary hypertension

“…After each procedure, the sheath and catheter were removed from the jugular vein. Because partial recovery of PAP between each injection day described previously was observed consistently, this treatment was repeated approximately once a week until the sPAP and mPAP values prior to microsphere injection exceeded 30 and 20 mmHg, respectively [17]. Then, this condition (i.e.…”

“…CEPH was induced according to a modified version of a previously described method [17, 20]. Briefly, 300 µ m microspheres (GE Healthcare, Chicago, IL, U.S.A.) were injected into the pulmonary artery through the 4-Fr catheter monitoring PAP.…”