A Dynamic Sheep Model to Induce Pulmonary Hypertension and Right Ventricular Failure.

ABSTRACT

Decompensated right ventricular failure (RVF) in pulmonary hypertension (PH) is fatal, with limited medical treatment options. Developing and testing novel therapeutics for PH requires a clinically relevant large animal model of increased pulmonary vascular resistance and RVF. This manuscript describes the method to induce an ovine PH-RVF model that utilizes left pulmonary artery (LPA) ligation, progressive main pulmonary artery (MPA) banding, and insertion of an RV pressure line for monitoring. The PA cuff and RV pressure tubing are connected to subcutaneous access ports. This model of PH-RVF is a versatile platform to control not only the disease severity, but also the RV's phenotypic response. Subjects undergo progressive PA band adjustments twice per week for approximately 9 weeks with sequential measures of RV pressure, PA cuff pressures, and mixed venous blood gas (SvO2). Subjects can further be exercised on a livestock treadmill while hemodynamic parameters are captured. At the initiation and endpoint of this model, ventricular function and dimensions are assessed using echocardiography. In this model, RV mean and systolic pressure increased to 28 ± 5 and 57 ± 7 mmHg at week 1, and further to 44 ± 7 and 93 ± 18 mmHg by week 9, respectively. Echocardiography demonstrates characteristic findings of PH-RVF, notably RV dilation, increased wall thickness, and septal bowing. The rate of PA banding has a significant impact on SvO2 and thus the model can be titrated to elicit varying RV phenotypes. When the PA cuff is tightened rapidly, it can lead to a precipitous decline in SvO2, leading to RV decompensation, whereas a slower, more paced strategy leads to an adaptive RV stress-load response that maintains physiologic SvO2. A faster rate of PA banding will also lead to more severe liver fibrosis. The addition of controlled exercise provides a useful platform for assessing the effects of physical exertion in a PH-RVF model. This chronic PH-RVF model provides a valuable tool for studying molecular mechanisms, developing diagnostic biomarkers, and evaluating mechanical circulatory support systems.