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

Abstract

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.

Figure 1:

Surgical steps to PH development: a) Left mini-thoracotomy is made. b) MPA is isolated with an umbilical tape. c) A silicone vascular occluder cuff is placed around the main distal PA. d) A pressure tubing is placed in the RVOT and secured with pledgeted suture. e) The LPA is ligated with an umbilical tape (white arrow: knot). f) The vascular occluder cuff connected to a subcutaneous port. The step number above each panel corresponds to the step-by-step guide provided under Supplementary Method 1.

Figure 2:

Chronic progressive PA banding: a) Sheep is placed in the transport cage to limit its mobility during banding. b) A Huber needle, a syringe with 3% hypertonic saline, and a three-way stopcock are used to access and control the occluder cuff. c) Both occluder and RV ports are accessed. d) Pressure traces from RV and cuff are obtained from their respective ports. The step number above each panel corresponds to the step-by-step guide provided under Supplementary Method 1.

Figure 3:

Changes in a) RV systolic pressure, b) respiratory rate, and c) heart rate over the two-month PH-RVH development period in four sheep. A weekly value was determined by taking the average across each week. The dotted lines in each plot represent the normal value or range in sheep.