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A Large Animal Model for Pulmonary Hypertension and Right Ventricular Failure: Left Pulmonary Artery Ligation and Progressive Main Pulmonary Artery Banding in Sheep

Decompensated right ventricular failure (RVF) in pulmonary hypertension (PH) is fatal, with limited medical treatment options. Developing and testing ...

Vanderbilt University Medical Center

Pulmonary hypertension (PH) is a progressive disease that leads to cardiopulmonary dysfunction and right heart failure from pressure and volume overloading of the right ventricle (RV). Mechanical cardiopulmonary support has theoretical promise as a bridge to organ transplant or destination therapy for these patients. Solving the challenges of mechanical cardiopulmonary support for PH and RV failure requires its testing in a physiologically relevant animal model. Previous PH models in large animals have used pulmonary bead embolization, which elicits unpredictable inflammatory responses and has a high mortality rate. We describe a step-by-step guide for inducing pulmonary hypertension and right ventricular hypertrophy (PH-RVH) in sheep by left pulmonary artery (LPA) ligation combined with progressive main pulmonary artery (MPA) banding. This approach provides a controlled method to regulate RV afterload as tolerated by the animal to achieve PH-RVH, while reducing acute mortality. This animal model can facilitate evaluation of mechanical support devices for PH and RV failure.

Left Pulmonary Artery Ligation and Chronic Pulmonary Artery Banding Model for Inducing Right Ventricular-Pulmonary Hypertension in Sheep.

Decompensated right ventricular failure (RVF) in patients with pulmonary hypertension (PH) is fatal, with limited treatment options. Novel mechanical circulatory support systems have therapeutic potential for RVF, but the development of these devices requires a large animal disease model that replicates the pathophysiology observed in humans. We previously reported an effective disease model of PH in sheep through ligation of the left pulmonary artery (PA) and progressive occlusion of the main PA. Herein, we report a case of acute decompensation with this model of chronic RVF. Gradual PA banding raised the RV pressure (maximum RV systolic/mean pressure = 95 mmHg/56 mmHg). Clinical findings and laboratory serum parameters suggested appropriate physiologic compensation for 7 weeks. However, mixed venous saturation declined precipitously on week 7, and creatinine increased markedly on week 9. By the 10th week, the animal developed dependent, subcutaneous edema. Subsequently, the animal expired during the induction of general anesthesia. Post-mortem evaluation revealed several liters of pleural effusion and ascites, RV dilatation, eccentric RV hypertrophy, and myocardial fibrosis. The presented case supports this model's relevance to the human pathophysiology of RVF secondary to PH and its value in the development of novel devices, therapeutics, and interventions.

Jennifer Talackine

Department of Thoracic Surgery

Vanderbilt University Medical Center

A Large Animal Model for Pulmonary Hypertension and Right Ventricular Failure: Left Pulmonary Artery Ligation and Progressive Main Pulmonary Artery Banding in Sheep