Progression Toward Decompensated Right Ventricular Failure in the Ovine Pulmonary Hypertension Model

Abstract

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.

Figure 1:

The animal’s physiologic parameters during the disease development: A) PA cuff internal pressure, B) RV mean (black diamond) and systolic (blue square) pressure measurements, C) respiratory rate, D) heart rate

Figure 2:

The animal’s blood laboratory values during the disease development: A) plasma levels of cardiac troponin I (CTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and atrial natriuretic peptide (ANP); B) serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT); C) blood levels of creatinine and blood urea nitrogen (BUN); D) white blood cell count. E) Mixed venous oxyhemoglobin saturation (S_vO₂) and hemoglobin level. Week 0 values were measured before initiating PH development.

Figure 3:

Clinical presentation and gross pathology of the animal near the end of progressive PH development: A) Brisket edema formation observed on the 69^th day of the disease model; B) Necropsy photographs of the heart (top left), lungs (top right), and liver (bottom)

Figure 4:

Histological findings in the lungs and liver are consistent with decompensated RV failure by the ovine PH model: A) H&E and Masson’s trichrome stains of left and right ventricles (40x magnification); B) H&E stains of left lung, right lung, and liver (left images at 20x magnification, right images at 100x (lung) and 200x (liver) magnification).